The first glance at Nanobi­otix’s re­cent round of da­ta for its drug NBTXR3 re­vealed pos­i­tive, but not pow­er­ful, da­ta when used against soft tis­sue sar­co­ma. The p val­ues were with­in the mark for sta­tis­ti­cal sig­nif­i­cance, but just bare­ly. So I asked sar­co­ma ex­pert George Demetri from Dana-Far­ber if he would take a look and give me his opin­ion.

Demetri took his dig­i­tal high­lighter and went to work on the biotech’s PR, scor­ing the re­sults and of­fer­ing re­marks on var­i­ous as­pects of the com­pa­ny state­ment that I found il­lu­mi­nat­ing. Rather than in­ter­pret them, I thought it would be more fun to re­pro­duce the whole thing here, with his com­ments high­light­ed in ital­ics.

NANOBI­OTIX An­nounces Pos­i­tive Phase II/III Topline Da­ta in Soft Tis­sue Sar­co­ma with NBTXR3

Paris, France and Cam­bridge, Mass­a­chu­setts, June 21, 2018 — NANOBI­OTIX (Eu­ronext: NANO – ISIN: FR0011341205), a late clin­i­cal-stage nanomed­i­cine com­pa­ny pi­o­neer­ing new ap­proach­es in the treat­ment of can­cer, an­nounced to­day pos­i­tive topline re­sults of the Phase II/III act.in.sarc tri­al eval­u­at­ing NBTXR3 in Soft Tis­sue Sar­co­ma (STS).

“Da­ta are ex­cep­tion­al and show with­out any doubt an im­prove­ment of ra­di­a­tion ther­a­py im­pact with a sig­nif­i­cant num­ber of com­plete re­sponse. NBTXR3 can bring re­al ben­e­fit to pa­tients and it can change the stan­dard of care. This in­no­va­tion will play a role in many oth­er in­di­ca­tions and par­tic­u­lar­ly where ra­dio­ther­a­py is used alone.”

Pr. Sylvie Bon­va­l­ot, MD, Head of Sar­co­ma and Com­plex Tu­mor Surgery Unit at In­sti­tut Curie, Paris, France and Glob­al Prin­ci­pal In­ves­ti­ga­tor of the PII/III study.

NBTXR3 is a first-in-class prod­uct with a new mode of ac­tion phys­i­cal­ly de­stroy­ing can­cer cells when ac­ti­vat­ed by ra­di­a­tion ther­a­py. NBTXR3 is de­signed to di­rect­ly de­stroy tu­mors and ac­ti­vate the im­mune sys­tem for both lo­cal con­trol and sys­temic dis­ease treat­ment.

The Phase II/III study was a prospec­tive, ran­dom­ized (1:1), multi­na­tion­al, open la­bel and ac­tive con­trolled two-armed study of 180 pa­tients with lo­cal­ly ad­vanced STS.

The ob­jec­tive of the Phase II/III tri­al was to eval­u­ate the ef­fi­ca­cy and the safe­ty of NBTXR3 ac­ti­vat­ed by ra­dio­ther­a­py com­pared to the stan­dard of care (ra­dio­ther­a­py alone). Pa­tients have been treat­ed with the stan­dard dose of ra­di­a­tion (25×2 Gy) and ef­fi­ca­cy end­points have been mea­sured on sur­gi­cal­ly re­sect­ed tu­mors.

Pri­ma­ry end­point achieved in the in­tend-to-treat pop­u­la­tion (ITT)

The pri­ma­ry end­point is the patho­log­i­cal Com­plete Re­sponse Rate (pCRR) de­fined as the rate of pa­tients show­ing less than 5% …

… of resid­ual vi­able can­cer cells in the tu­mor post treat­ment. This pri­ma­ry end­point is re­lat­ed to NBTXR3’s mode of ac­tion and prod­uct ef­fi­ca­cy. Twice as many pa­tients (16.1% vs 7.9%) achieved a patho­log­i­cal Com­plete Re­sponse (pCR) with NBTXR3 com­pared to the con­trol arm (p = 0.0448).

The sig­nif­i­cant dif­fer­ence ob­served be­tween both arms val­i­dates the su­pe­ri­or­i­ty of the treat­ment with NBTXR3 ver­sus ra­di­a­tion alone.

Sec­ondary End­point achieved in the ITT – Re­sec­tion mar­gins sta­tus and op­er­abil­i­ty

The main sec­ondary end­point is the re­sec­tion mar­gin sta­tus eval­u­at­ing the qual­i­ty of surgery. The main ob­jec­tive is to achieve com­part­men­tal clean mar­gins (neg­a­tive mar­gin de­fined as R0) i.e. no more can­cer cells found with­in the sur­gi­cal mar­gins. NBTXR3 demon­strat­ed a sta­tis­ti­cal­ly sig­nif­i­cant in­crease in R0 sur­gi­cal mar­gin rate com­pared to ra­dio­ther­a­py alone (rel­a­tive in­crease of 20%, p = 0.042).

The re­sec­tion with neg­a­tive mar­gins is a val­i­dat­ed sur­ro­gate end­point for sys­temic and long-term ben­e­fit for pa­tients such as lo­cal pro­gres­sion free sur­vival (PFS) and dis­tant PFS.

Pr Jean-Yves Blay, MD, Di­rec­tor of the Cen­tre Léon Bérard, Ly­on, France, com­ment­ed, “I am amazed by the dif­fer­ence of Re­sponse Rate, it is ex­treme­ly un­com­mon to dou­ble the Rate of Com­plete his­to­log­i­cal Re­sponse and I do not see any oth­er strat­e­gy able to ac­com­plish that. Even more im­pres­sive is the R0 rate, which is in­creased by more than 20% com­pared to an av­er­age rate of 64%. This dif­fer­ence is re­al­ly im­pres­sive, con­sid­er­ing that R0 im­pacts pa­tients re­laps­es and sur­vival.”

Safe­ty and fea­si­bil­i­ty

NBTXR3 demon­strat­ed a good lo­cal tol­er­ance among this pa­tient’s pop­u­la­tion. Find­ings showed a very sim­i­lar ra­di­a­tion-re­lat­ed safe­ty in both arms. The pa­tients in both the con­trol and test­ed arms of the study re­ceived the planned ra­dio­ther­a­py (dose and sched­ule).

No­tably, fea­si­bil­i­ty and fol­low-up of surgery were al­so equiv­a­lent. Acute im­mune ad­verse events of short du­ra­tion ob­served in 7.9% of pa­tients.

The In­jec­tion site caused pain in 13.5% of pa­tients. In ad­di­tion, 6.7% of pa­tients ex­pe­ri­enced grade 1 in­jec­tion site hematoma / ec­chy­mo­sis.

Re­gard­ing long-term tox­i­c­i­ty, less se­ri­ous ad­verse events were re­port­ed for NBTXR3 arm.

Reg­u­la­to­ry strat­e­gy and CE mark

The pos­i­tive re­sults from this study sup­port and fur­ther val­i­date the Eu­ro­pean reg­u­la­to­ry strat­e­gy of the pre­vi­ous­ly sub­mit­ted CE mark­ing ap­pli­ca­tion in STS. The com­pa­ny will sub­mit the new da­ta as a sup­ple­ment to the Eu­ro­pean No­ti­fied Body in a time­ly man­ner.

Next steps

The Com­pa­ny will present the re­sults at an up­com­ing in­ter­na­tion­al med­ical con­fer­ence.

The clin­i­cal val­i­da­tion of NBTXR3’s phys­i­cal mode of ac­tion in a very het­ero­ge­neous and hard-to-treat dis­ease strength­ens the uni­ver­sal pro­file of the prod­uct and con­firms the de­vel­op­ment strat­e­gy in mul­ti­ple in­di­ca­tions.

Cur­rent­ly, the com­pa­ny is eval­u­at­ing NBTXR3 in sev­en clin­i­cal tri­als with a fo­cus on head and neck can­cers and Im­muno-On­col­o­gy pro­grams.

David Raben MD, Pro­fes­sor of Ra­di­a­tion On­col­o­gy, Uni­ver­si­ty of Col­orado Can­cer Cen­ter, CO, USA, com­ment­ed, “These re­sults from a Phase III study are im­pres­sive in a no­to­ri­ous­ly dif­fi­cult dis­ease like Soft Tis­sue Sar­co­ma. These can­cers are gen­er­al­ly less sen­si­tive to ra­di­a­tion and pre­vi­ous at­tempts to im­prove lo­cal con­trol with chemo-ra­di­a­tion reg­i­mens were con­sid­ered too tox­ic. This study sub­stan­ti­ates the med­ical ben­e­fit of safe­ly en­hanc­ing the ef­fect of ra­di­a­tion ther­a­py with nov­el physics-based ap­proach­es de­liv­ered lo­cal­ly with­in the can­cer. In ad­di­tion, this prod­uct may po­ten­ti­ate a pro-in­flam­ma­to­ry en­vi­ron­ment suit­able for im­mune en­abling or DNA dam­age in­hibitor drugs. These find­ings set the foun­da­tion for ad­di­tion­al stud­ies in ar­eas such as head and neck can­cer and per­haps in ar­eas such as high-risk prostate, blad­der or pan­creas can­cer.”

Im­age: George Demetri. PHAR­MA­MAR via YOUTUBE

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