#AACR: Bris­tol-My­ers tunes out sta­t­ic, broad­casts im­pres­sive re­sults for Op­di­vo/Yer­voy lung can­cer com­bo

CHICA­GO — Bris­tol-My­ers Squibb $BMY ran smack dab in­to a high lev­el of pro­fes­sion­al sta­t­ic when it changed up its study de­sign for Check­mate-227, a piv­otal test for Op­di­vo plus Yer­voy in treat­ing new cas­es of non-small cell lung can­cer. But they’ve ar­rived at AACR with da­ta they say spell out a com­pelling case for their PD-1/CT­LA-4 com­bo.

Fouad Namouni

“The da­ta we re­port here are ex­cit­ing,” says Fouad Namouni, the on­col­o­gy de­vel­op­ment chief at Bris­tol-My­ers, “with an im­por­tant lev­el of ac­tiv­i­ty.”

Their drug re­duced the risk of pro­gres­sion or death by 42% with a haz­ard ra­tio of 0.58.

At the one-year mark, Namouni told me in a pre­view of to­day’s re­lease, the pro­gres­sion-free sur­vival rate in the com­bo arm was 43%, com­pared to on­ly 13% in the con­trol arm. And that’s re­gard­less of PD-L1 ex­pres­sion sta­tus and his­tol­ogy, with no changes for squa­mous or non­squa­mous cas­es.

Re­searchers in­volved in the study ripped up the orig­i­nal tri­al de­sign, mesh­ing da­ta to­geth­er and claim­ing a suc­cess against a nov­el goal for pa­tients with a “high tu­mor mu­ta­tion bur­den.” And they went their own way on defin­ing the TMB so that it in­clud­ed close to half of all pa­tients in the pop­u­la­tion, rather than the more min­i­mal sub­group tracked by the test mak­er Foun­da­tion Med­i­cine, which us­es a bar that is set twice as high to clas­si­fy pa­tients.

Clear­ly, Namouni says, this marks a big ad­vance for pa­tients — to say noth­ing about their in­tense ri­val­ry with Mer­ck. And he adds that it makes sense.

“A high tu­mor mu­ta­tion bur­den is a sur­ro­gate for neo-anti­gens,” he adds, which makes the tu­mor more vis­i­ble to the im­mune sys­tem, and in turn makes it more like­ly to be re­spon­sive to a PD-1/L1 check­point.

Their work here, says Namouni, in­volves deep­en­ing the field’s un­der­stand­ing of the bi­ol­o­gy of lung can­cer. 

They’ve al­so got ev­i­dence to back up their po­si­tion that 10 mu­ta­tions/megabase is the right in­flec­tion point, rather than mov­ing the scale up even as high as 15. The Foun­da­tion test sets the mark at 20.

For some ri­vals, that kind of as­ser­tion looks like a boast that can’t be proven at this ear­ly stage of the game. But in a chat with As­traZeneca’s David Berman, their chief of I/O pro­grams, he agreed that their own work backed up the stan­dard used by Bris­tol-My­ers — not­ing that in lung can­cer specif­i­cal­ly 10 mu­ta­tions/megabase marked the right cut­off for the as­say on high TMB. Every can­cer type is dif­fer­ent, he adds, and they’ve been care­ful­ly study­ing this them­selves in their work on dur­val­um­ab in lung can­cer.

There are oth­er prob­lems that are pre­sent­ed by us­ing the test, though. One is that it cur­rent­ly takes about 2 weeks to get back re­sults on the tu­mor mu­ta­tion bur­den, and some crit­ics say pa­tients and doc­tors may not want to de­lay ther­a­py to run the test. But Bris­tol-My­ers’ Namouni says that that is with­in the usu­al con­sul­ta­tion time it takes to de­cide on ther­a­py — adding that what takes 2 weeks now could be quick­ly sliced back to a cou­ple of days with the prop­er fo­cus.

Bris­tol-My­ers’ ap­proach may con­tin­ue to raise hack­les among some ob­servers — but this is a high­ly re­spect­ed R&D or­ga­ni­za­tion that is de­ter­mined to re­main a leader in lung can­cer, come what may or might at Mer­ck or any of its oth­er ri­vals.

Namouni says they’ve been in con­ver­sa­tions with reg­u­la­to­ry groups about the da­ta, but he isn’t of­fer­ing any time­lines on fil­ings. 

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Vas Narasimhan. Getty Images

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Back in July, during an investor call where Novartis execs ran through an upbeat assessment of their Q2 performance, CEO Vas Narasimhan and development chief John Tsai were pressed to predict which of the two looming Phase III readouts — involving cardio drug Entresto and asthma therapy fevipiprant, respectively — had a higher likelihood of success. Tsai gave the PARAGON-HF study with Entresto minimally better odds, but Narasimhan emphasized that their strategy of giving fevipiprant to more severe patients gave them confidence.

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David Liu, Liu Group

David Liu un­veils newest ad­vance­ment in CRISPR tech: Prime edit­ing

The researcher behind base-editing is out with what some scientists are hailing as the biggest advancement in CRISPR technology since that 2016 breakthrough: “prime editing.” The new molecular gadget is capable of erasing any base pair and stenciling in another and cutting or adding long segments of DNA without breaking both strands of the helix.

David Liu, base editing pioneer and founder of Beam Therapeutics, published the findings in Nature alongside Andrew Anzalone. They estimated that the breakthrough “in principle” puts 89% of human diseases in purview — although experts cautioned that human therapies were a long way off.

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HBM Healthcare Investments, Vivo Capital, BlackRock, Omega Funds, Pivotal BioVentures, and Goldman Sachs jumped on board, joining Bain Capital Life Sciences, OrbiMed and RA Capital Management in backing Arcutis’ lead topical cream for plaque psoriasis.

A new com­pa­ny en­ters the Tec­fidera fight, of­fer­ing to kill two birds

The remedy for the most common side effect for one of the most common multiple sclerosis drugs is simple: aspirin.

Taking aspirin with Biogen’s Tecfidera will reduce the flush, a sometimes painful form of red skin irritation, many patients experiences. The problem is that the aspirin has to be taken at least 30 minutes before Tecfidera, turning a simple twice-a-day, one-dose oral drug into a staggered two-drug regimen.

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Despite a head start, when Bristol-Myers Squibb and its pioneering checkpoint inhibitor Opdivo suffered a key lung cancer setback in 2016, they found themselves relegated to the backseat as Merck’s Keytruda seized the wheel on the road to immunotherapy stardom. Bristol-Myers has since suffered blow after blow in its quest to take a big slice of the lucrative market, peppered with some small successes. On Tuesday, the New Jersey drugmaker touted positive data from a Phase III open-label study in a bid to carve itself a piece of the frontline lung cancer market.

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Sometime in the 1st century AD, a patient presented to Arataeus looking like a varicose ghost. He was “emaciated and atrophied, pale, feeble and incapable of performing any of his accustomed works,” the Greek physician wrote, with hollow temples and huge veins running all over his body.

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IM­brave150: Roche’s reg­u­la­to­ry crew plans a glob­al roll­out of Tecen­triq com­bo for liv­er can­cer as PhI­II scores a hit

Just weeks after Bristol-Myers Squibb defended its failed pivotal study pitting Opdivo against Nexavar in liver cancer, Roche says it’s beat the frontline challenge with a combination of their PD-L1 Tecentriq with Avastin. And now they’re rolling their regulatory teams in the US, Europe and China in search of a new approval — badly needed to boost a trailing franchise effort.
Given their breakthrough and Big Pharma status as well as the use of two approved drugs, FDA approval may well prove to be something of a formality. And the Chinese have been clear that they want new drugs for liver cancer, where lethal disease rates are particularly high.
Researchers at their big biotech sub, Genentech, say that the combo beat Bayer’s Nexavar on both progression-free survival as well as overall survival — the first advance in this field in more than a decade. We won’t get the breakdown in months of life gained, but it’s a big win for Roche, which has lagged far, far behind Keytruda and Opdivo, the dominant PD-1s that have captured the bulk of the checkpoint market so far.
Researchers recruited hepatocellular carcinoma — the most common form of liver cancer — patients for the IMbrave150 study who weren’t eligible for surgery ahead of any systemic treatment of the disease.
Roche has a fairly low bar to beat, with modest survival benefit for Nexavar, approved for this indication 12 years ago. But they also plan to offer a combo therapy that could have significantly less toxicity, offering patients a much easier treatment regimen.
Cowen’s Steven Scala recently sized up the importance of IMbrave150, noting:

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