Behandling med enbart checkpointhämmare har haft liten effekt vid platinaresistent återkommande äggstockscancer. Orsaken finns i tumörmikromiljön. Där anrikas TNFR2-positiva regulatoriska T-celler och myeloida celler, som håller CD8 T-cellerna borta. BI-1808 är utformad för att rensa ut de suppressiva cellerna och släppa in T-cellerna igen. BioInvent har därför testat den tillsammans med pembrolizumab i en pågående fas I/IIa-studie, och de data från del B som presenterades vid ESMO i helgen är den första fullständiga avläsningen från äggstockscancerkohorten.
Responser hos en kraftigt förbehandlad grupp
Samtliga av de 34 utvärderingsbara patienterna hade fått platinabehandling efter i median fyra tidigare behandlingslinjer bakom sig. Åtta svarade på behandlingen, en komplett och sju partiella responser, vilket ger en responsfrekvens på 24 %. Som jämförelse nådde enbart pembrolizumab 8 % i studien KEYNOTE-100. Sjukdomskontrollen nådde 53 %, och flera patienter hade stabil sjukdom i över tio månader. Sex av dem stod fortfarande på behandling vid brytdatumet.
Vid en medianuppföljning på 11,6 månader hade medianvaraktigheten för responserna ännu inte uppnåtts, och responser sågs vid både höggradigt serös och klarcellig sjukdom, inklusive hos vissa patienter med aktiva levermetastaser.
Bland de 81 patienter med solida tumörer som har fått BI-1808 tillsammans med pembrolizumab avbröt färre än 5 % behandlingen på grund av biverkningar, och allvarliga biverkningar var ovanliga. Immundata stämde med verkningsmekanismen: färre regulatoriska T-celler i blodet, och i tumörbiopsier en förskjutning mot CD8 T-celler samt tecken på att tertiära lymfoida strukturer bildas.
En ny grund för del C
Del C bygger på att standardbehandlingen nyligen har förändrats. Studien KEYNOTE-B96 visade att tillägg av pembrolizumab till veckovis paklitaxel förbättrade överlevnaden jämfört med enbart cytostatika, ett sällsynt positivt resultat i denna svårbehandlade patientgrupp.
BioInvent vill nu bygga vidare på den grunden. I del C randomiseras 20 patienter till var och en av tre studiearmar: BI-1808 1 000 mg, BI-1808 500 mg eller kontrollsubstans. Studien förväntas starta under första kvartalet 2027, med första data under andra halvåret samma år. BI-1808 har redan FDA Fast Track Designation för äggstockscancer.
Q&A med BioInvents medicinska chef
BioStock bad Andres McAllister att gå igenom vad data från del B visar, och vad som väntar för programmet under det kommande året.
The response rate came in at 24 percent, three times the 8 percent for pembrolizumab alone. What does a difference like that mean clinically?
– Platinum-resistant ovarian cancer is a setting where patients have few options and where checkpoint inhibitors alone have mostly disappointed. At 8 percent, roughly one patient in twelve responds. At 24 percent it’s closer to one in four. For a patient, that is the difference between a drug that rarely shrinks the tumor and one that does so with some regularity. We also see this in a population that is heavily pretreated, so the bar is high.
– I’d add two cautions. This is a single-arm study compared against a historical benchmark, so we are careful about drawing hard conclusions. Response rate is also only one measure, and what matters in the end is duration of benefit. But a tripling of the response rate, achieved without chemotherapy and with very few treatment discontinuations due to side effects, is a signal worth taking seriously.
You have worked on this mechanism for years. With Part B now complete, what stands out most to you in the data?
– What stands out is how well the clinical picture matches the biology we have been describing. TNFR2 is highly expressed on regulatory T cells in the tumor, and BI-1808 is designed to deplete them and to reprogram myeloid cells, which should make a PD-1 inhibitor work better. When we see responses in a setting where PD-1 blockade has historically done little, and we see the biomarker changes you would expect, such as a shift in the balance between CD8 T cells and Ttregs in tumor biopsies, that is a coherent story.
– The second thing is that the activity holds across both high-grade serous and clear cell subtypes, which are quite different diseases. And the safety profile has stayed clean across a large body of patients, which matters a great deal when you want to build on top of the combination.
One of the responders had already progressed on pembrolizumab in an earlier line. What does it tell you that the combination worked where the checkpoint inhibitor alone had not?
– This is exactly the kind of case you hope to see if the mechanism is real. If a tumor has already shown it can escape PD-1 blockade alone, and adding a Treg-depleting, myeloid-reprogramming antibody produces a response, it suggests that BI-1808 is contributing something the checkpoint inhibitor was not providing, rather than simply riding along with it. It supports the idea that Treg-mediated suppression is one of the things holding these tumors back.
Why add chemotherapy in Part C after a chemotherapy-free Part B, and how did KEYNOTE-B96 shape that decision?
– Part B was designed to answer a clean question: does BI-1808 add something to pembrolizumab on its own? It does appear to, and that was important to establish without the confounding effect of chemotherapy.
– KEYNOTE-B96 changed the landscape, though. It showed that pembrolizumab with weekly paclitaxel is a meaningful step forward in platinum-resistant ovarian cancer, and it is becoming the reference regimen. So the relevant question for patients and physicians is no longer only how we compare with pembrolizumab alone, but whether we can improve on the new standard. Chemotherapy can also help release tumor antigens and prime the immune system, which fits well with what BI-1808 does. Part C is therefore a randomized comparison, with BI-1808 at two dose levels, against pembrolizumab plus weekly paclitaxel with or without bevacizumab, which is how the regimen is used in practice.
– We think the chemotherapy-free combination remains valuable for patients who cannot tolerate chemotherapy, and Part C addresses the larger group where the standard of care now sits.
Which upcoming readouts or decisions around BI-1808 do you see as the most important over the next 12 to 18 months?
– First, the full Part B dataset, which we expect before the end of this year. That will tell us whether the 24 percent holds as the numbers grow and give us more mature durability data, including by subtype.
– Second, the start of Part C, which we expect to begin enrolling in the first quarter of 2027, with initial data in the second half of 2027. That is the most important readout, because it is randomized and it will also help us choose the dose.
– Third, the regulatory and partnering side. The FDA’s Fast Track designation for ovarian cancer gives us closer dialogue with the agency about what a registrational path could look like, and the data from Part C will shape those discussions. Alongside this, we continue to develop BI-1808 in T-cell lymphoma, where it has orphan drug designation, so there are several ways this program can move forward.
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