Alligator Bioscience har presenterat en andra omgång interimsresultat från en fas II-studie med mitazalimab i patienter med bukspottkörtelcancer. Den uppföljande utvärderingen av de första 23 patienterna visar en objektiv svarsfrekvens på 57 procent – en ökning från 52 procent vid den första utvärderingen som rapporterades i januari. Utvärderingen av hela uppsättningen av 57 patienter visar en objektiv svarsfrekvens på 44 procent – en siffra som kan komma att förbättras. Fler datapunkter indikerar att mitazalimab ger ett varaktigt svar i kombination med standardbehandlingens kemoterapi. För en fördjupad analys vände sig BioStock till Alligators CMO Sumeet Ambarkhane.

Fas II-studien OPTIMIZE-1 utvärderar Alligator Biosciences ledande tillgång mitazalimab i metastaserad bukspottkörtelcancer. I studien utvärderas CD40-agonisten som en första linjens behandling i kombination med mFOLFIRINOX – den vanligaste kemoterapin för patienter med bukspottkörtelcancer.

I början av 2023 presenterade Alligator lovande data från en första interimsanalys av studien som utvärderade de första 23 patienterna. Under ett webbinarium med Key Opinion Leader (KOL) som leddes av bolagets CMO Sumeet Ambarkhane, påpekade studiens huvudprövare, Jean-Luc Van Laethem, att det primära effektmåttet – den objektiva responsfrekvensen (ORR) – uppnåddes med ett mått på 52 procent vid den tidpunkten. Detta var redan signifikant högre än den tidigare uppmätta ORR på cirka 30 procent för enbart mFOLFIRINOX.

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En andra interimsanalys

I veckan meddelade Alligator resultaten av en andra interimsanalys, som inkluderade samtliga de 57 patienter som gick att utvärdera och som rekryterats till studien. För att diskutera resultaten och sätta dem i perspektiv av det nuvarande behandlingslandskapet i bukspottskörtelcancer var Alligator värd för en KOL-webbsändning med Zev Wainberg, professor i medicin vid University of California, Los Angeles (UCLA) och meddirektör för UCLA Gastrointestinal (GI) Oncology Program.

Den andra interimsanalysen visar att bland de 23 patienterna från den första utvärderingen ökade ORR från 52 till 57 procent när fler patienter började svara på behandlingen. Av de 13 patienter som svarat på behandlingen har sju (54 procent) stått på behandling längre än 10 månader och upp till 17 månader. Enligt professor Wainberg är detta en indikation på varaktigheten av svaret på mitazalimab i kombination med kemoterapi.

I detta sammanhang hänvisade professor Wainberg till mediandurationen av respons (DoR), som mättes till 8,7 månader för patienter som svarade på kombinationen mitazalimab/kemo. Detta är högre än 5,9 månaders DoR för enbart FOLFIRINOX som rapporterats i tidigare studier. Det är också högre än de 3,9 månader som rapporterats med gemcitabin + nab-paklitaxel – en annan standardbehandling som används hos patienter med metastaserad bukspottkörtelcancer.

CMO kommenterar

BioStock kontaktade Alligators CMO Sumeet Ambarkhane för att få en bättre förståelse för resultaten och vad de betyder för utvecklingen av mitazalimab.

Dr Ambarkhane, how do the latest data compare to the data you presented in January?

– The latest data are based on the complete enrolled cohort for the study, and hence confirm the well-manageable safety profile as well as the very promising signal of clinical efficacy that was indicated in the January data. We also see an early, but very meaningful trend indicating the durable nature of responses in this data set which is very reassuring and could in theory translate in Progression Free Survival and Overall Survival benefit.

In the data readout, we see results from the initial cohort of 23 patients and then results from the full cohort of 57 patients. For those who have not been following the study closely, could you explain how the study is designed and why we are looking at two different sets of results for this second interim analysis?

– While the data from the full cohort of 57 patients represent the overall study population, it has the limitation that the length of treatment and follow up for the majority of the patients is insufficient at this time of analysis. Whereas the treatment and follow up for the initially reported 23 patients is considerably longer. Thus, the updated data on these initial 23 patients give an indication of how the overall cohort outcomes are likely to evolve towards the top-line readout in January 2024, with similarly longer treatment and follow up duration. At the end, the whole trial will of course be analysed and interpreted as a single cohort.

Of all 57 patients, ORR was measured at 44 per cent, so slightly lower than the 52 per cent measured after the first analysis with 23 patients alone. Is this in line what you would expect?

– As professor Wainberg mentioned in the webcast, the response rate represents disease evaluation at a given point in time, and this is quite dependent on whether patients have received sufficiently long treatment. This being an interim analysis only a few months after completion of recruitment, many patients had received only a few treatment cycles and are ongoing in treatment. Thus, the currently reported response rate also has this limitation and should not be interpreted as a definitive outcome. This is underscored by the increase in the response rate in the more mature 23-patient cohort. Nonetheless, this response rate is sufficient to confirm the meaningful clinical activity of the mitazalimab-mFOLFIRINOX combination treatment as was reported in the previous analysis. For these reasons, the primary analysis that will be reported early next year will be more conclusive.

What other data points stood out to you from the second interim analysis?

– What particularly stands out to me as a physician is the deepening of response with maintained treatment and its durable nature in several patients. Many patients were able to continue the mitazalimab immunotherapy together with the mFOLFIRINOX chemotherapy for several months longer than what is typical for chemotherapy alone. This points strongly to an immune activating effect of mitazalimab in these patient – in line with our expectations.

During the KOL webcast, Prof. Wainberg talks about the fact that the data so far do not give a snapshot of progression free survival (PFS). Could you expand on this point?

– Indeed. Progression free survival reflects the length of time for which the tumour is kept under control before it starts to grow again. There needs to be a considerably longer duration of treatment as well as follow up after the trial for each patient, to allow for a meaningful analysis of progression free survival. The upcoming primary analyses of the trial will address this to a great extent. We are very encouraged by the fact that several patients are still ongoing in treatment after six to nine months (four to six months is the typical length of mFOLFIRINOX therapy) and this combined with much improved Duration of Response may very likely translate in a meaningful extension of PFS compared to FOLFIRINOX alone.

Is the study still on track for top-line results at the beginning of next year?

– Yes, very much so, the study activities are all on track and the team is well prepared to accomplish these analyses as planned.

Finally, how encouraged are you by this second interim analysis of OPTIMIZE-1?

– Personally, I believe in mitazalimab’s potential even more than before with these analyses. The well manageable safety as well as durability of responses we are observing potentially differentiate mitazalimab from other CD40-based therapeutic approaches, allowing long-maintained treatment with mitazalimab in combination with chemotherapy. In an extremely aggressive malignancy such as pancreatic cancer an extended durability of response would be a highly desirable effect, potentially translating into extended survival. These data also strongly point toward the need of mitazalimab-containing combination regimens to be evaluated in other tumour types to maximise its development potential and value.

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