Dr. Serrano (European sarcoma key opinion leader) was confident that Bex would show efficacy in sarcoma and referred to it as “low hanging fruit.” This term previously came up in Juho’s communications back when the FDA still had a more lenient approach to granting conditional approvals regarding r/r MDS. Now an external expert is justifying it in his presentation. Three patients have already been recruited, meaning the first dose cohort is full and the next one is starting.
“We believe that we now have a drug candidate capable of challenging the standard of care in sarcoma, doxorubicin monotherapy, which has prevailed for three decades.”
So far, no toxicity or safety issues have been observed. Things seem to be moving at a good pace, the timeline is being tightened, but truly finalized results will take time, although preliminary ones are expected as early as next spring.
Moving from story to execution.
Summary
Slide 1
Thank you, Petri, for the very kind introduction, and hello everyone. Over the next few minutes, my goal is to explain why targeting Clever-1 in sarcoma patients is important and why I believe this is a prime target (“low-hanging fruit”). You may have heard about this before, but Clever-1 is a type of protein expressed primarily and almost exclusively on the surface of myeloid-lineage cells. Under physiological conditions, Clever-1 serves several beneficial functions in the body, but problems arise in cancers where it promotes tumor growth. This occurs mainly by altering leukocyte trafficking and inhibiting T-cell activation, which creates an immunosuppressive microenvironment that shields the tumor (a pro-tumorigenic effect). It is already well established that high Clever-1 expression in cancers correlates with a poorer prognosis and promotes tumor treatment tolerance. This is based on clinical studies demonstrating an association between Clever-1 protein expression, its encoding gene STAB1, and patient outcomes. Next slide, please.
Slide 2
The rationale for inhibiting the STAB1 gene or the Clever-1 protein in sarcoma is biologically very solid. We previously analyzed all tumors profiled in the TCGA database to check STAB1 gene expression. We found that among solid tumors, sarcomas along with mesothelioma are the two tumor types with the highest STAB1 gene expression. In sarcomas, expression levels are widespread, creating a very compelling and strong rationale for targeting STAB1. This finding also supports numerous studies published in the field in recent years. The predominant immune cell infiltrate in sarcomas consists of macrophages that sustain an immunosuppressive tumor environment. Thus, a strong link is established between the immunosuppressive microenvironment of sarcomas, macrophage predominance, and high STAB1 gene expression. Next.
Slide 3
Sarcoma encompasses multiple subtypes. These six subtypes shown here represent approximately 80% of all sarcomas. In our preliminary RNA expression study, we observed differences in STAB1 expression across various sarcoma subtypes. The three subtypes shown on the right side express higher levels of the STAB1 gene, and these three subtypes are also the most common sarcomas treated with cytotoxic chemotherapy in daily clinical practice. These findings serve as the foundation for the design of the upcoming clinical trial, which I will discuss in a moment. Next, please.
Slide 4
What are sarcomas? Sarcomas are tumors of mesenchymal origin. There are nearly 70 different subtypes and roughly 150 mesenchymal tumor entities in total. A major challenge in managing these patients is that primary localized disease is treated mainly with surgery and potentially radiation therapy. Once the disease spreads—i.e., metastasizes, which occurs in over half of patients—treatment has remained unchanged for three decades: primarily doxorubicin and anthracyclines. The problem with doxorubicin is its relatively modest efficacy: the overall response rate is only 10–15%, and median progression-free survival is 6–8 months. The two most recent clinical trials challenging doxorubicin monotherapy (top right in the table) failed to meet their primary endpoints. This indicates they were not the right combinations, yet it proves that conducting such comparative trials is feasible in the sarcoma field. Sarcomas exhibit a broad spectrum of subtypes that clinicians can attempt to target with various precision therapies (such as TKIs), but we lack biomarkers to guide their use. Therefore, we face major challenges in treating these patients, and outcomes have not improved over the past 2–3 decades. Next.
Slide 5
This provides the context for why targeting Clever-1 in sarcoma represents an exceptionally promising opportunity (“low-hanging fruit”). First, Clever-1 biology supports this: among solid tumors, sarcomas exhibit the highest STAB1 gene expression, and this expression is highest precisely in the most common sarcoma types. Second, patient prognosis with current decades-old drugs remains poor, and therapeutic efficacy is very modest. Next.
Slide 6
Why combine chemotherapy with Bex? In clinical trials combining chemotherapy with immune checkpoint inhibitors, efficacy in soft tissue sarcoma has been very limited. This is because the microenvironment is already intrinsically too immunosuppressive for PD-1 inhibitors alone, either as monotherapy or in combination. We also know that chemotherapy can prime tumors for immune responses and further upregulates Clever-1 expression. Therefore, there is a strong biological rationale that combining cytotoxic chemotherapy with immunotherapy can maximize treatment response and improve patient outcomes. Next.
Slide 7
I would also like to share some data supporting these assertions. First, Clever-1 blockade combined with chemotherapy holds broad potential, and sarcoma could serve as one of its key proof-of-concept indications. It has been shown that many chemotherapy regimens can increase infiltration of STAB1-expressing macrophages, leading to an even more immunosuppressive tumor microenvironment. Clinical data (top) also demonstrate that high STAB1 expression following neoadjuvant therapy in ovarian cancer worsens prognosis. Meanwhile, the Sun Sun cohort study from Shanghai (bottom) confirms that high Clever-1 expression in the tumor environment correlates with poorer prognosis regardless of disease stage.
Mouse models provide further evidence that Bex shifts the TME to become less immunosuppressive and mitigates the myelosuppressive effects of chemotherapy.
The evidence of Clever-1 protein expression in sarcoma, the finding that chemotherapy induces Clever-1 expression, and the macrophage-driven immune infiltrate expressing Clever-1—coupled with the high unmet medical need and clinical trial feasibility in sarcoma—led to this ongoing Phase 1b/2 trial in Spain. The trial evaluates the combination of first-line standard-of-care doxorubicin and BEX.
Currently, the dose escalation phase is underway, followed by a dose expansion phase. If target endpoints are met, the study will proceed as a randomized Phase 2 clinical trial. The second cohort in dose escalation has opened. The doxorubicin dose is fixed at 75 mg/m², as BEX has demonstrated an excellent tolerability profile. The doxorubicin dose remains constant while BEX dose levels are escalated.
Following dose escalation, the expansion phase will commence, followed by Phase 2. The expansion phase will enroll only soft tissue sarcoma subtypes represented in the TCGA database to validate anticipated Clever-1 expression and combination efficacy. Thanks to the CAP design implemented, highly meaningful efficacy data will be generated despite a relatively modest patient sample size. Positive results will prompt transition into a randomized trial using the same study design.
Treatment comprises 6 cycles of doxorubicin in combination with BEX, followed by BEX maintenance therapy. Primary endpoints include determining the maximum tolerated dose (MTD) and safety/tolerability profile, alongside efficacy indicators. In Phase 2, the primary endpoint will be progression-free survival (PFS).
Clinical trial progress: the first dose cohort (3 patients) has completed. Recruitment is ongoing for the second dose level, with investigators actively looking to open additional sites. Preliminary results are anticipated in April–May 2027. The objective is to compress the timeline to have a complete dataset ready for the Phase 2 trial by early 2029.
Investigators consider the biological rationale exceptionally strong. The goal is to develop a therapeutic agent capable of challenging the three-decade standard of care established by doxorubicin monotherapy in sarcoma.
Questions and Answers (Q&A)
Petri:
Thank you, Cesar, fantastic progress; the first cohort is completed. Let’s take questions from the webcast.
Question:
After many years of sarcoma research, what gives you confidence that targeting Clever-1 with BEX can succeed where previous approaches yielded only limited results?
Cesar Serrano:
What provides the greatest confidence is that soft tissue sarcomas exhibit the highest STAB1 gene expression among all solid tumors. Previous combinations (such as olaratumab, other chemotherapies, or small-scale PD-1 inhibitor studies) lacked a functional biomarker. Sarcomas with complex genomics (which are the most common) express very high levels of STAB1.
Question / Petri:
What would represent a clinically meaningful improvement compared to chemotherapy monotherapy alone in Phase 1b?
Cesar Serrano:
The goal centers on two endpoints:
1. The response rate of doxorubicin monotherapy is low (10–15%). Doubling the response rate to around 25% would be a major milestone (comparable to a two-drug chemotherapy combination).
2. Immunotherapy can significantly prolong disease control. Extending progression-free survival (PFS) from 6–8 months to roughly 12 months (a full year) would be a remarkable achievement for patients whose disease typically progresses rapidly.
. Toi oli lähinnä note to self, kun kehtasin epäillä, saavatko kongresseille mitään aikaiseksi, kun sitä jo oli lupailtu.