No OS ben­e­fit? No prob­lem. FDA pan­el backs use of Lyn­parza in pan­cre­at­ic can­cer

As As­traZeneca works to tight­en its hold on the PARP mar­ket, an in­de­pen­dent pan­el of ad­vi­sors to the FDA cau­tious­ly en­dorsed Lyn­parza’s use in cer­tain pan­cre­at­ic can­cer pa­tients, even though it failed to help pa­tients live longer.

On Tues­day, pan­elists vot­ed 7-5 to rec­om­mend the drug for main­te­nance use in pa­tients with germline BR­CA-mu­tat­ed metasta­t­ic ade­no­car­ci­no­ma of the pan­creas, whose dis­ease has not pro­gressed on at least 16 weeks of first-line plat­inum-based chemother­a­py. Glob­al­ly, germline BR­CAm pan­cre­at­ic can­cer ac­counts for 5-7% of all cas­es.

The FDA is not oblig­ed to ac­cept the rec­om­men­da­tions of the pan­el but typ­i­cal­ly does. The agency is ex­pect­ed to make its fi­nal de­ci­sion in the fourth quar­ter.

Lyn­parza, known chem­i­cal­ly as ola­parib, is al­ready ap­proved as a main­te­nance agent in mul­ti­ple lines of ther­a­py for ovar­i­an can­cer, as well as a metasta­t­ic breast can­cer ther­a­py. It is al­so ex­pect­ed to se­cure ap­proval in prostate can­cer next year.

The pan­cre­at­ic can­cer ap­pli­ca­tion was based on the 154-pa­tient, place­bo-con­trolled PO­LO tri­al. Lyn­parza in­duced a sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment in pro­gres­sion-free sur­vival (PFS) (95% con­fi­dence in­ter­val: 0.35, 0.81; p=0.0035) — cor­re­spond­ing to a 3.6-month im­prove­ment in me­di­an PFS. There was al­so ev­i­dence of tu­mor shrink­age, in­di­cat­ed by the dif­fer­ence in the over­all re­sponse rate of 9.9% ver­sus the place­bo arm. How­ev­er, no ef­fect on over­all sur­vival (OS) was ob­served.

In a brief­ing doc­u­ment post­ed days ear­li­er, FDA staff high­light­ed their con­cerns about the drug’s use in this pan­cre­at­ic can­cer pop­u­la­tion. Re­view­ers took is­sue that the pri­ma­ry end­point was as­sessed on the ba­sis of tu­mor mea­sure­ments, which can dif­fer among tu­mor set­tings and are sub­ject to as­sess­ment bias. In ad­di­tion, they ques­tioned whether the tri­al was ‘ad­e­quate­ly con­trolled’ giv­en its small size. An­oth­er source of un­cer­tain­ty, they said, was the lim­i­ta­tions of cur­rent imag­ing tech­nol­o­gy to ac­cu­rate­ly mea­sure the ef­fect on PFS.

“Giv­en these con­cerns re­gard­ing the ac­cu­ra­cy of tu­mor mea­sure­ment in pan­cre­at­ic can­cer, FDA ap­proval of all pre­vi­ous drugs for the treat­ment of pan­cre­at­ic can­cer has been based on ef­fects on OS, an end­point for which as­sess­ment bias and lim­i­ta­tions in the ac­cu­ra­cy of tu­mor mea­sure­ment by imag­ing tech­nol­o­gy are not present,” the re­port said.

“FDA ac­knowl­edges that a dif­fer­ence in PFS fa­vor­ing the ola­parib arm has been demon­strat­ed in the PO­LO tri­al. How­ev­er, there is un­cer­tain­ty that the ob­served mag­ni­tude of the treat­ment ef­fect on PFS ac­cu­rate­ly rep­re­sents the true treat­ment ef­fect…”

As­traZeneca and part­ner Mer­ck’s Lyn­parza, akin to GSK’s Ze­ju­la and Clo­vis On­col­o­gy’s Rubra­ca, is a poly-ADP ri­bose poly­merase (PARP) in­hibitor. PARP is a pro­tein used by dam­aged cells to ini­ti­ate re­pair, and by thwart­ing it, the class of drugs is en­gi­neered to pre­vent can­cer cells from re­pair­ing them­selves, there­by cat­alyz­ing their de­struc­tion.

“While there are cur­rent­ly 4 ap­proved PARP in­hibitors in the US and Eu­rope, As­traZeneca and part­ner Mer­ck have es­tab­lished the drug as the mar­ket leader through a com­bi­na­tion of mar­ket­ing ex­per­tise and strate­gic tri­al de­signs,” SVB Leerink’s An­drew Berens wrote in a note last month.

“We ex­pect the drug to re­main the mar­ket leader…with po­ten­tial ex­pan­sion to oth­er tu­mors like pan­cre­at­ic, blad­der and lung,” he said, adding that ex­perts ex­pect Lyn­parza to con­tin­ue as the dom­i­nant PARP in­hibitor un­til its loss of ex­clu­siv­i­ty, which is mod­eled for 2029.

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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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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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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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.

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.

Take­da scores a win for a rare type of lung can­cer, gear­ing up for a show­down with J&J

Four months after J&J’s infused drug Rybrevant scored the industry’s first win in a rare type of non-small cell lung cancer (NSCLC), Takeda is following up with an oral option for the small but desperate patient population.

The FDA granted an accelerated approval to Takeda’s oral TKI inhibitor Exkivity (mobocertinib) in metastatic NSCLC patients with EGFR exon 20 gene mutations who had previously undergone platinum-based chemotherapy, the company announced on Wednesday.

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