Förstår inte vad du menar. Kan du förklara det på ett annat sätt?
Altså.
Alt dette var så enkelt.
Helt til det viste seg
å være sykt komplisert.
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For å kunne vise dette er ikke FOCUS-studien i så måte feil-designet siden den kun rekrutterer PD-L1 positive pasienter ?
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De får ikke ipi da 
Men ja, du har et poeng.
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Jeg ser ellers i referatet fra Q3-22 at både Jens og Carlos kommenterte dette med at UV1 kan være spesielt egnet for sub-gruppen PD-L1 negative. For Initium så kan det kanskje virke utfra det Carlos sier at det spesielt er dataene i tilleggsstudien de vil analysere dette.
Jens (under presentasjonen) :
In malignant melanoma, it’s allowed to treat all patients with different checkpoint inhibitors. So we do not do any biomarker analysis prior to inclusion or treatment of patients. Nevertheless, in the large studies that has been conducted, and the scientists have tried to understand if there are groups of patients that respond better to checkpoint inhibitors than others. And it has been seen that if you are – have a high levels of PD-L1 expression, one of these biomarkers, you can expect in a group of patients to have better response than in those patients with a lower PD-L1. When we added the vaccine on top of pembrolizumab in our study, we did not see this difference. Actually, in those patients with a low PDL1 expression, we saw an even higher response rate compared to those patients with a high PDL1 expression. This is also something we did with other biomarkers like tumor mutation burden, interferon gamma signature, et cetera, and we saw the same pattern with all the biomarkers used by the scientists to have some kind of view on checkpoint treatment alone.
Og fra et spm under Q&A :
You have done nice work with the PD-L1 biomarker to support the efficacy and overall universal approach. Does this translate outside of this trial and have a broader implication?
Jens :
Yes. So I also am curious about that. So the interesting thing here is that, remember, when you are using the CPIs, you are, in a way, even if that is very not maybe not very scientific to say it that way, but you are opening the tumor for the pre-existing immune system. So in some patients, they will have a sufficient T cell repertoire to kill off the can tumor to push the patient into a complete response. In other patients they do not have the sufficient number and quality of T cells that can help them into a complete response. So our thinking is that when you add a T cell that can be recognized tumors in all patients in the indication, telomerase is expressed in all melanoma patients, for example. We expect that the immune system will be relevant for more patients. So also in those patients with a low PD-L1 indicating to some extent that they have fewer relevant T cells because then the tumor doesn’t need to protect itself with PD-L1. Also in those patients, we see good efficacy when we add the vaccine on top. Remember that this is only a few patients, but we will follow up on this in this indication and also in other indications. It would be very good if we could add a general vaccine on top of CPIs, also have a possibility to treat this hard-to-treat patients in the future.Carlos :
And if I can just make an additional comment. As we inform all of you, we have this extension study to the INITIUM where we are going to be in a more controlled way, really make all these collection of samples to do further examination. And of course, one of them is going to be the PD-L1 expression. So as that part of that extension study progresses and later next year, we will have additional more data. But this is, we believe this is a very exciting finding. It’s a small group of patients. But as Jens mentioned, shows that maybe patients that normally wouldn’t respond to pembrolizumab will respond with the addition of UV1. And this is more relevant in some other indications where the PD-L1 expression in reality defines which treatment the patients are going to receive. Like for instance, in non-small cell lung cancer, if the patients are low expressers of PD-L1, they cannot just receive pembrolizumab alone, they have to add chemotherapy. So this is areas where we see that as we collect more information, it can be very exciting to see if we can expand the pool of patients that will benefit of adding UV1 to the checkpoint inhibitor.
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Enig, veldig rart at PD-L1-negative er utelatt fra FOCUS. Selvskudd?
Andel negative, fra 103-studien:
4 av 9 CR
5 av 12 PR
5 av 9 PD
Dvs
9 av 21 PR/CR
Små tall, man kan ikke konkludere. Trenger profilering av enkeltpasienter for å se helheten.
Vel verdt å merke seg at alle PR/CR i 103 hadde lav TMB. Ingen med PD. Det er en såpass tydelig trend at selv med små tall bør det være vitenskapelig interessant å se nærmere på.
Frustrerende å lese dette og samtidig se at FOCUS ekskluderer PD-L1-negative. Mistenker bias andre veien, nemlig at ICI funker best med positive, og at UV1 skal gi enda mere gass for disse pasientene. Jeg mistenker at den antakelsen er feil.
Considering the encouraging read-out, the study population was assessed to determine whether it was biased toward those expected to benefit from pembrolizumab. Baseline biopsies were evaluated for several biomarkers associated with clinical outcomes of checkpoint inhibition.
Remarkably, patients achieving clinical responses to the combination did not exhibit higher PD-L1 expression, higher TMB, a large volume of predicted immunogenic neoantigens, enrichment of the IFNg gene signature, or higher tumor-infiltrating lymphocytes, all of which are measures of immunologically active tumors and have shown some degree of predictive value for CPI efficacy in melanoma in previous studies (5, 9, 27–29). Indeed, for patients with PD-L1–negative tumors, the KEYNOTE-006 trial showed an ORR of only 24% (95% CI, 16.4%–33.7%) with 5.8% achieving CR (30). In the UV1–103 study, the combination treatment yielded an ORR of 57% in this subgroup of patients, with 35.7% reaching iCR. The median TMB in the present study population was 6.6 mutations/Mb (range, 1.3–55.2). While higher TMB is associated with improved clinical response to pembrolizumab in melanoma (28), clinical responders in the UV1–103 trial exhibited lower TMB than nonresponders (3.0 vs. 10.7 mutations/Mb; P value ¼ 0.246)
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Guda meg, de har mye å svare for, ledelsen…
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Har det kommet lyd fra Gaudernack om INITIUM?
Ikke sett annet enn det lille han sa til DN dagen etter meldingen :
Gaudernack sier til DN at han fortsatt er optimistisk med tanke på forskningen Ultimovacs driver med.
– Jeg bryr meg ikke om et eventuelt børstap for min egen del. Jeg er aller mest opptatt av at disse vaksinene kommer frem til pasientene.
Takker. Jeg tenkte mest på om det var noen vitenskapelige halmstrå på gang fra Ullernchaussen 
Pembro mono i HNSCC er kun godkjent for PD-L1 positive. Det forklarer nok inklusjonskriteriene i FOCUS.
Det er likevel ganske snodig å utelate de negative da det kunne åpnet en ny mulighet for pembro og gitt et ekstra kjøpsargument for Merck
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Er resultatene interessante så kan vel det uansett tas med i neste runde?
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UV1 ser ikke ut til å bry seg om PD-L1-status. Derfor jeg mener alle burde vært med. Ideelt sett tre armer,
pembro mono, pembro + UV1, pembro + UV1 + chemo (som er SoC for negative i dag)
Ja, kan inkluderes i neste studie, men det er litt kjipt å ikke få se hele potensialet
Jag påstår inte att jag förstår allt, inte ens i närheten av det. Men jag försöker i alla fall analysera och förstå. Men jag förstår bra mycket mer än absolut ingenting, som du påstår.
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Du gir inntrykk av at du vet og nærmest latterliggjør de som fortsatt har tro på UV1.
Samtidig drar du konklusjoner basert på egne tolkninger som strider mot alle historiske studier og tilgjengelig data.
Jeg har ikke inntrykk av at du prøver å lære, men all ære til de som tror på det og gir av sin tid til deg.
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Gikk avlesningen åt skogen på feil premisser ? Kan du förklara det på ett annat sätt?
INITIUM menar du? INITIUM failade bara helt enkelt.
Lol så pga att jag för dig framstår auktoritär, är det att likställa med att jag skulle påstå att jag vet allting? Hahaha. Ser du inte att problemet ligger hos dig och inte hos mig?
Vänligen visa mig:
- Konklusioner man dragit avseende korrelationen mellan immunrespons och radiologisk respons.
- Att man relativiserat eller tillbakavisat de stapeldiagram man stolt skyltat med avseende ORR, ffa i IPI4-armen, men även i UV-103 (man för dock en liten diskussion om det i den publicerade artikeln)
Det är du som inte försöker lära dig någonting. Om du hade gjort det hade du nyfiket lyssnat på den enda kritiska rösten som orkade argumentera mot ett helt forum fullt av haussare och som försökte tona ner graden av masspsykosen innan allt gick åt pipsvängen.
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Da konkluderer du samtidig med at SoC har blitt himla mye bedre, Lars. Tidligere studier og aggregerte real world data er bare bullshit. 🫣
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