Scandion Oncology har meddelat uppdaterade positiva interimsresultat från den tredje och sista delen av den pågående fas IIa-studien CORIST med SCO-101 i metastaserad kolorektalcancer. BioStock kontaktade bolagets CMO, Lars Damstrup, som menar att tidiga tecken på förbättrad total överlevnad är en viktig parameter för regulatoriska myndigheter inför kommande fas IIb-studier.

Scandion Oncology utvecklar läkemedel för behandling av kemoterapiresistent metastaserad kolorektalcancer (mCRC) respektive bukspottkörtelcancer där läkemedelsresistens drabbar 90 procent av patienterna, vilket innebär att de är resistenta mot nuvarande behandlingsalternativ.

Huvudkandidaten SCO-101 utvärderas i fas II- och Ib-studierna CORIST och PANTAX. I CORIST behandlas heavily pre-treated mCRC-patienter med SCO-101 i kombination med cellgiftsbehandlingen FOLFIRI, som för närvarande är standardbehandlingen för denna indikation.

Fas II-studien CORIST

Scandion kunde redan vid inledningen av 2024 meddela positiva topline-resultat från den pågående tredje delen av fas II-studien CORIST. Resultaten visade inte bara på en tumörenreducering och en väsentligt ökad progressionsfri överlevnad, det pekade även på att SCO-101 – i kombination med FOLFIRI – leder till en hög klinisk nytta samtidigt som behandlingen är säker och tolereras av patienterna.

En påföljande analys av top line-data visade att Clinical Benefit Rate (CBR) ökade till från 46 procent i del två av CORIST – till 76 procent efter åtta veckors behandling i del tre. En av patienterna uppvisade en markant tumörreducering på över 30 procent. Tumören tycktes med andra ord minska eller stabiliseras, ju längre behandlingen pågår. I början av mars kunde bolaget konstatera att ytterligare en patient har haft en partiell respons med en tumörminskning på mer än 30 procent.

Därmed har en klinisk nytta påvisats i totalt två av sex patienter i den sista studiekohorten. Vd Francois Martelet framhöll i en intervju med BioStock att resultatet är imponerande med tanke på den mycket höga dödligheten i sjukdomen.

»Overall, these results further strengthen the positive data from CORIST part 2 and the earlier data from CORIST 3« — Lars Damstrup, CMO Scandion Oncology

CMO kommenterar

Den 21 mars kunde Scandion Oncology presentera ytterligare uppdaterade positiva interimsresultat från den sista och tredje delen av CORIST.

Bolaget har nu utforskat optimerade dosscheman vilket resulterade i förväntade förändringar i exponering mot SCO-101 och cellgiftsbehandlingen FOLFIRI. Dessutom kunde en ny potentiell biomarkör, genotypen UGT1A1, kopplas till längre progressionsfri överlevnad och total överlevnad.

BioStock kontaktade bolagets Chief Medical Officer Lars Damstrup för en kommentar.

Lars, can you discuss the overall findings of the interim results?

— Overall, these results further strengthen the positive data from CORIST part 2 and the earlier data from CORIST 3. We reported that we now have two partial responses in the SCO-101 250 mg cohort in the 4-day schedule. At this dose of SCO-101 we did not see any dose limiting toxicity. This further substantiates that SCO-101 in combination with FOLFIRI is well tolerated.

How do the optimized dosing schedules affect exposure to SCO-101 and FOLFIRI?

— The optimized dosing schedules in Part 3 included a different timing of FOLFIRI in relation to SCO-101 than what was used in Part 1 and 2. It also included a 6-day and a 4-day administration of SCO-101. Furthermore, the dose of the 5FU component in the FOLFIRI was increased from 50% to 100% of the recommended standard dose. Compared to Part 1, we observed that the optimized dosing schedules resulted in a minor reduction in the peak value (Cmax) for the active metabolite of irinotecan, named SN-38, by roughly 20% compared to in Part 1. Additionally, the SCO-101 initial peak was higher compared to Part 1.

— This slight reduction of SN-38 and the higher peak initial peak of SCO-101 was what we hoped to observe since this would be predicted to cause less toxicity from SN-38 and a stronger initial SCO-101 target engagement. The overall exposure to SN-38 and SCO-101 was roughly the same as in Part 1. However, the optimized design allowed to increase the SCO-101 dose to 250 mg in a 4-day schedule and in this specific cohort, we observed proof-of-concept anti-cancer effects as 2 of the six patients in this cohort had partial tumour reductions, which are rarely observed in this patient population.

The novel potential biomarker was positively associated with longer progression free survival and overall survival. Why is this important for the upcoming development steps?

— We have analysed two potential biomarkers in CORIST: The bilirubin index (BI) and the genotype of UGT1A1. In CORIST Part 2, we observed that patients with a low BI had a significantly longer median OS. This was reflected in CORIST Part 3 by demonstrating that a low BI is associated with longer PFS and OS. In CORIST Part 3, we analyzed a novel potential biomarker, the UGT1A1 genotype. The biological reasoning is that SCO-101 targets UGT1A1 and that patients with fully functional UGT1A1 (i.e. UGT1A1 wild-types) would respond better to SCO-101. Topline data in CORIST Part 3 supports this rationale since patients with UGT1A1 wild-type appeared to have longer PFS and OS than patients with mutated UGT1A1. Importantly, the CORIST Part 3 data are interim and we plan to report the final data in H2 2024.

— With these potential biomarkers, we may be able to select patients who will benefit the most from the combination of SCO-101 and FOLFIRI. We will ultimately select the right biomarker based on the outcome of the randomized Phase 2b clinical trial.

What makes overall survival the gold standard in oncology trials, and how would regulatory authorities perceive indications of enhanced overall survival in CORIST?

— Overall survival is a gold standard in oncology as it is a hard endpoint which can easily be ascertained. In some situations, for example, first line treatment overall survival can be very long. Therefore, in these cases, progression-free survival may be a valid primary endpoint. In last line treatment of patients with colorectal cancer, overall survival is up to 1 year. This means that overall survival is the preferred primary endpoint in this disease and line of therapy.

Finally, the next step on your roadmap entails broadening part 3 data with additional smaller patient cohorts to further optimise the dosing regimen. When can we expect results from these cohorts?

— Our ultimate goal is to conduct a randomized clinical trial in this patient population. At this point in time, we have a safe and tolerated dose of SCO-101 given in the 4-day schedule in combination with FOLFIRI where irinotecan is given at 50% of the standard dose and 5-FU and folinic acid is given at 100%.

— In preparation for the best dose to be implemented in the randomized phase 2a, we will increase the dose of irinotecan from 50% to 65 and ultimately to 80%. This will be done in the classical manner with a 3+3 design.

— It is difficult to pin-point the time for data read out from this as it depends on when we see signs of toxicity.

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