Can­cer tri­als aimed at 'sur­ro­gate' tar­gets miss big­ger mark — study

Find a ran­dom per­son on the street and ask them what a can­cer drug should do. What are the odds they don’t say “it should help pa­tients live health­i­er and longer”?

A con­flu­ence of forces have pushed clin­i­cal tri­als away from that seem­ing­ly cen­tral ques­tion, with de­vel­op­ers and pa­tient groups bet­ting on the promise that aim­ing at more sub­tle mea­sures can help bring need­ed ther­a­pies to mar­ket faster. But a new study from the British Med­ical Jour­nal sug­gests the con­ven­tion­al wis­dom may be right and that trend, among oth­ers, have led can­cer drugs to hit the mar­ket based off stud­ies that have a high risk of bias.

Re­searchers led by Lon­don School of Eco­nom­ics Pro­fes­sor Huseyin Naci tracked can­cer drug ap­provals by the Eu­ro­pean Med­ical As­so­ci­a­tion over three years from 2014 to 2016. Putting aside 13 tri­als not based on a ran­dom­ized con­trol mod­el — which have their own set of is­sues but can be use­ful for rare dis­eases — and two tri­als with­out pub­lished da­ta, they eval­u­at­ed 39 tri­als that formed the ba­sis of drug ap­provals in that pe­ri­od ac­cord­ing to a stan­dard cri­te­ria of bias and found: 19 (49%) were at high risk of bias and the ones that didn’t look at im­prov­ing sur­vival were more like­ly to be at risk. On­ly 10 tri­als pri­mar­i­ly looked at im­prov­ing sur­vival.

Among them, 20% of tri­als that looked at over­all sur­vival had a high risk of bias, com­pared to 55% of the rest.

Oth­er fac­tors be­sides end­point were at play in stud­ies at risk for bias, in­clud­ing miss­ing da­ta and red flags in how da­ta were mea­sured, such as the tri­al lack­ing a blind­ed as­sess­ment.

But in their dis­cus­sion of the re­sults, the au­thors fo­cused in part on the pauci­ty of tri­als that looked head-on at whether a drug will help pa­tients sur­vive, warn­ing that tri­als that look at oth­er “sur­ro­gate” end­points speed up de­vel­op­ment but might mis­lead pa­tients and bring drugs that don’t work. Eval­u­at­ing the study in a BMJ opin­ion col­umn, Bar­bara Mintzes and Agnes Vit­ry took sim­i­lar aim.

“Un­cer­tain­ty and ex­ag­ger­a­tion of the ev­i­dence that sup­ports ap­proval of can­cer drugs caus­es di­rect harm if pa­tients risk se­vere or fa­tal ad­verse ef­fects with­out like­ly ben­e­fit,” they wrote. “Or for­go more ef­fec­tive and safer treat­ments.”

The push to­ward these “sur­ro­gate” mea­sures has come from both de­vel­op­ers, ea­ger to get their treat­ments to mar­ket, and pa­tient groups hop­ing to se­cure ac­cess to new reme­dies as fast as pos­si­ble. Tar­get­ing over­all sur­vival on av­er­age takes about an ex­tra year, time many can­cer pa­tients don’t have.

A fed­er­al law, the 21st Cen­tu­ry Cures Act, that went in­to ef­fect in 2017 cod­i­fied that push. Yet da­ta on tri­als that avoid the cen­tral ques­tion of elon­gat­ing and im­prov­ing qual­i­ty of life have been mixed.

A 2018 JA­MA In­ter­nal Med­i­cine re­view of 52 ar­ti­cles cov­er­ing 38 tri­als on a to­tal of 14,000 pa­tients with 12 dif­fer­ent can­cers from 2000 through 2016 found no sig­nif­i­cant as­so­ci­a­tion be­tween pro­gres­sion-free sur­vival and health-re­lat­ed qual­i­ty of life.

The study al­so comes as one of many crit­i­cal­ly eval­u­at­ing ex­ist­ing sci­en­tif­ic lit­er­a­ture in the wake of the repli­ca­tion cri­sis that broke out most pub­licly in psy­chol­o­gy and has rip­pled across the sci­ences. In 2012 Am­gen’s head of re­search, Glenn Be­g­ley, pub­lished a pa­per in Na­ture re­veal­ing a 10-year com­pa­ny ef­fort to re­pro­duce 53 “land­mark” stud­ies in on­col­o­gy. They got pos­i­tive re­sults in 6.

As­traZeneca trum­pets the 'mo­men­tous' da­ta they found for Tagris­so in an ad­ju­vant set­ting for NSCLC — but many of the ex­perts aren’t cheer­ing along

AstraZeneca is rolling out the big guns this evening to provide a salute to their ADAURA data on Tagrisso at ASCO.

Cancer R&D chief José Baselga calls the disease-free survival data for their drug in an adjuvant setting of early stage, epidermal growth factor receptor-mutated NSCLC patients following surgery “momentous.” Roy Herbst, the principal investigator out of Yale, calls it “transformative.”

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 81,800+ biopharma pros reading Endpoints daily — and it's free.

Ab­b­Vie wins an ap­proval in uter­ine fi­broid-as­so­ci­at­ed heavy bleed­ing. Are ri­vals My­ovant and Ob­sE­va far be­hind?

Women expel on average about 2 to 3 tablespoons of blood during their time of the month. But with uterine fibroids, heavy bleeding is typical — a third of a cup or more. Drugmakers have been working on oral therapies to try and stem the flow, and as expected, AbbVie and their partners at Neurocrine Biosciences are the first to make it across the finish line.

Known chemically as elagolix, the drug is already approved as a treatment for endometriosis under the brand name Orilissa. It targets the GnRH receptor to decrease the production of estrogen and progesterone.

David Chang, Allogene CEO (Jeff Rumans)

Head­ed to PhII: Al­lo­gene CEO David Chang com­pletes a pos­i­tive ear­ly snap­shot of their off-the-shelf CAR-T pi­o­neer

Allogene CEO David Chang has completed the upbeat first portrait of the biotech’s off-the-shelf CAR-T contender ALLO-501 at virtual ASCO today, keeping all eyes on a drug that will now try to go on to replace the first-wave personalized pioneers he helped create.

The overall response rate outlined in Allogene’s abstract for treatment-resistant patients with non-Hodgkin lymphoma slipped a little from the leadup, but if you narrow the patient profile to treatment-naïve patients — removing the 3 who had previous CAR-T therapy who didn’t respond, leaving 16 — the ORR lands at 75% with a 44% complete response rate. And 9 of the 12 responders remained in response at the data cutoff, offering a glimpse on durability that still has a long way to go before it can be completely nailed down.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 81,800+ biopharma pros reading Endpoints daily — and it's free.

Pablo Legorreta, founder and CEO of Royalty Pharma AG, speaks at the annual Milken Institute Global Conference in Beverly Hills, California (Patrick T. Fallon/Bloomberg via Getty Images)

Cap­i­tal­iz­ing Pablo: The world’s biggest drug roy­al­ty buy­er is go­ing pub­lic. And the low-key CEO di­vulges a few se­crets along the way

Pablo Legorreta is one of the most influential players in biopharma you likely never heard of.

Over the last 24 years, Legorreta’s Royalty Pharma group has become, by its own reckoning, the biggest buyer of drug royalties in the world. The CEO and founder has bought up a stake in a lengthy list of the world’s biggest drug franchises, spending $18 billion in the process — $2.2 billion last year alone. And he’s become one of the best-paid execs in the industry, reaping $28 million from the cash flow last year while reserving 20% of the cash flow, less expenses, for himself.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 81,800+ biopharma pros reading Endpoints daily — and it's free.

Fabrice Chouraqui, Cellarity CEO-partner (LinkedIn)

Drug de­vel­op­er, Big Phar­ma com­mer­cial ex­ec, now an up­start biotech chief — Fab­rice Chouraqui is ready to try some­thing new as a ‘CEO-part­ner’ at Flag­ship

Fabrice Chouraqui’s career has taken some big twists along his life journey. He got his PharmD at Université Paris Descartes and jumped into the drug development game for a bit. Then he took a sharp turn and went back to school to get his MBA at Insead before returning to pharma on the commercial side.

Twenty years later, after steadily rising through the ranks and journeying the globe to nab a top job as president of US pharma for the Basel-based Novartis, Chouraqui exited in another career switch. And now he’s headed into a hybrid position as a CEO-partner at Flagship, where he’ll take a shot at leading Cellarity — one of the VC’s latest paradigm-changing companies of the groundbreaking model that aspires to deliver a new platform to the world of drug R&D.

Paul Hudson, Sanofi CEO (Getty Images)

Sanofi CEO Paul Hud­son has $23B burn­ing a hole in his pock­et. And here are some hints on how he plans to spend that

Sanofi has reaped $11.1 billion after selling off a big chunk of its Regeneron stock at $515 a share. And now everyone on the M&A side of the business is focused on how CEO Paul Hudson plans to spend it.

After getting stung in France for some awkward politicking — suggesting the US was in the front of the line for Sanofi’s vaccines given American financial support for their work, versus little help from European powers — Hudson now has the much more popular task of managing a major cash cache to pull off something in the order of a big bolt-on. Or two.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 81,800+ biopharma pros reading Endpoints daily — and it's free.

Roger Perlmutter, Merck R&D chief (YouTube)

UP­DAT­ED: Backed by BAR­DA, Mer­ck jumps in­to Covid-19: buy­ing out a vac­cine, part­ner­ing on an­oth­er and adding an­tivi­ral to the mix

Merck execs are making a triple play in a sudden leap into the R&D campaign against Covid-19. And they have more BARDA cash backing them up on the move.

Tuesday morning the pharma giant simultaneously announced plans to buy an Austrian biotech that has been working on a preclinical vaccine candidate, added a collaboration on another vaccine with the nonprofit IAVI and inked a deal with Ridgeback Biotherapeutics on an early-stage antiviral.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 81,800+ biopharma pros reading Endpoints daily — and it's free.

As­traZeneca’s $7B ADC suc­ceeds where Roche failed, im­prov­ing sur­vival in gas­tric can­cer

Another day, another win for Enhertu.

The antibody-drug conjugate AstraZeneca promised up-to $7 billion to partner on has had a quite a few months, beginning with splashy results in a Phase II breast cancer trial, a rapid approval and, earlier this month, breakthrough designations in both non-small cell lung cancer and gastric cancer.

Now, at ASCO, the British pharma and their Japanese partner, Daiichi Sankyo, have shown off the data that led to the gastric cancer designation, which they’ll take back to the FDA. In a pivotal, 187-person Phase II trial, Enhertu shrunk tumors in 42.9% of third-line patients with HER2-positive stomach cancer, compared with 12.5% in a control arm where doctors prescribed their choice of therapy. Progression-free survival was 5.4 months for Enhertu compared to 3.5 months for the control.

Once a gem, now just a rock, Take­da punts PhI­II IBD drug as ri­vals mus­cle ahead

Back in 2016, when then-Shire CEO Flemming Ørnskov picked up a promising clinical-stage IBD drug from Pfizer, the Boston-based biotech dubbed it SHP647 and moved it into the gem section of the pipeline, with rosy expectations of registration-worthy Phase III data ahead.

This was a drug that the EC wanted Takeda to commit to selling off before it gave their blessing to its acquisition of Shire, to settle some deep-seated concerns revolving around the potential market overlap with their blockbuster rival Entyvio. And Takeda, which took on a heavy debt load to buy Shire, clearly wanted the cash to pay down debt.