The Future of Rare Cancer Treatment | ESMO 2026

Rare and difficult-to-treat cancers provide an important test of precision oncology, where distinct tumor biology, small patient populations, and limited treatment options complicate drug development. By identifying actionable molecular alterations, comprehensive genomic profiling and transcriptomic analysis can help move treatment beyond histology towards more targeted, biomarker-driven strategies. The ESMO Congress 2026 offers an opportunity to assess progress across these challenges. Three themes stand out: the evolution from single-agent activity to biomarker-defined treatment strategies, the expanding role of Antibody-drug Conjugates (ADCs) across tumor types, and the investigation of PD-1/VEGF bispecific antibodies in rare malignancies. Together, these developments raise a broader question: can emerging therapies move beyond promising antitumor activity to deliver durable clinical benefit, identify patients more likely to respond, and establish new treatment options where unmet need remains high?

Uveal melanoma: Can targeted therapy extend beyond metastatic disease? 

Uveal melanoma has distinct molecular drivers and a high risk of metastatic spread, yet systemic treatment options remain limited. Against this backdrop, IDEAYA Biosciences and Servier are advancing darovasertib, a Protein Kinase C (PKC) inhibitor, in combination with crizotinib, towards potential regulatory review, potentially opening a new targeted-treatment avenue for this underserved population. In the registrational Phase II/III OptimUM-02 trial in first-line HLA-A*02:01-negative disease, median Progression-Free Survival (PFS) was 6.9 months with the combination vs. 3.1 months with investigator's choice therapy (hazard ratio 0.42), and the Objective Response Rate (ORR) was 37.1% vs. 5.8%. Overall survival data were immature at the primary analysis. The company states that no therapy is approved for this HLA-negative population, and a US new drug application is underway under real-time oncology review.

At ESMO 2026, the focus shifts from efficacy to patient selection and clinical applicability. The OptimUM-02 subgroup analysis will help assess whether benefit extends across clinically relevant subsets, while OptimUM-01 will provide further evidence in HLA-A*02:01-positive metastatic disease. Earlier overall survival estimates from OptimUM-01 remain difficult to interpret against historical controls and cannot replace randomized evidence. Meanwhile, OptimUM-09 explores whether neoadjuvant darovasertib can influence outcomes in primary uveal melanoma. Across these studies, response durability, safety, and the consistency of benefit will be critical to defining the combination’s clinical potential.

Osteosarcoma and Soft Tissue Sarcoma: Can Novel ADCs and Immunotherapy Combinations Address Persistent Treatment Gaps?

Sarcomas encompass diverse tumor subtypes with distinct molecular drivers and treatment responses, making a one-size-fits-all approach challenging. At ESMO 2026, two studies highlight different strategies to address unmet needs: B7-H3-targeted ADCs in relapsed or refractory osteosarcoma and immunotherapy-based neoadjuvant treatment in Soft Tissue Sarcoma (STS).

Osteosarcoma: Could B7-H3-Targeted ADCs Reshape Salvage Treatment?

Late-breaking abstract LBA9 (Presidential Symposium III, 26 October 2026) will present Phase III ARTEMIS-011 results for risvutatug rezetecan (ris-rez), a B7-H3-directed ADC with a topoisomerase I inhibitor payload, vs. gemcitabine/docetaxel in heavily pretreated relapsed or refractory osteosarcoma. The sponsor has reported that the China phase III trial met its primary endpoint of independently assessed PFS, with consistent benefit on secondary endpoints including overall survival. The magnitude of benefit remains undisclosed and will determine the clinical significance.

Earlier Phase II ARTEMIS-002 findings showed encouraging activity, without an apparent relationship between B7-H3 expression and response. Ris-rez has also demonstrated promising results in relapsed SCLC, with median OS of 18.5 vs. 10.3 months for topotecan in Phase III ARTEMIS-008 (HR 0.46; WCLC 2026).

The key question is whether these results establish B7-H3 as a cross-tumor therapeutic target. LBA9 will be important for assessing the magnitude and durability of benefit, safety in a heavily pretreated population, and the applicability of China-generated data to global practice. With GSK holding development rights outside China, the findings could also shape the ADC's broader development strategy.

Soft Tissue Sarcoma: Can Neoadjuvant Immunotherapy Preserve Quality of Life?

In soft tissue sarcoma, treatment strategies that improve disease control without adding substantial treatment burden are an important area of investigation. ESMO 2026 will feature abstract 3788eP, reporting health-related quality of life (HRQoL) data from EFTISARC-NEO, an investigator-initiated Phase II trial (NCT06128863) evaluating neoadjuvant eftilagimod alfa, pembrolizumab, and radiotherapy in patients with STS. The findings will be presented as an ePoster.

Eftilagimod alfa is an MHC Class II agonist designed to activate antigen-presenting cells and support antitumor immune responses. The combination investigates whether immune activation alongside pembrolizumab and radiotherapy can be incorporated into neoadjuvant treatment while maintaining patients’ quality of life.

Why it matters: HRQoL data can complement clinical outcomes by showing how patients experience treatment before surgery. However, this abstract focuses on quality of life; it should not be interpreted as proof of improved efficacy or as evidence that the combination is superior to standard treatment. The reported results will be important for understanding treatment tolerability and patient experience in this setting.

Thymic Carcinoma: Can Dual Immune and Angiogenic Targeting Address an Unmet Need?

Thymic carcinoma is a rare and aggressive malignancy for which treatment options remain limited, particularly when disease recurs or progresses after initial therapy. At ESMO 2026, abstract 4156RO will report interim results from the Phase II iTHYM study, evaluating ivonescimab plus chemotherapy as first-line treatment for recurrent or metastatic thymic carcinoma. Ivonescimab is a bispecific antibody that targets PD-1/VEGF-A, combining immune checkpoint inhibition with antiangiogenic activity in a single molecule. By targeting both immune suppression and tumor-associated angiogenesis, the combination aims to address two mechanisms that may contribute to tumor growth. However, the clinical value will ultimately depend on whether this dual approach translates into meaningful and durable disease control.

The key question is whether the combination can deliver more than an encouraging early response signal. Response rates and duration, PFS, treatment-related toxicity, and the maturity of follow-up will be essential to understanding the findings. Given the rarity of thymic carcinoma, the study could provide valuable evidence for further development, although interim results alone may not establish a new standard of care.

Why it matters: A positive signal could strengthen the case for investigating PD-1/VEGF bispecific antibodies in rare thoracic malignancies. More importantly, it could help define whether combining immune and angiogenic targeting offers a clinically meaningful strategy for patients with limited treatment options. The significance of the iTHYM results will therefore rest not simply on whether ivonescimab shows activity, but on how convincingly that activity translates into sustained patient benefit.

Extrapulmonary Neuroendocrine Carcinoma (EP-NEC): Could Opamtistomig Offer a New Treatment Strategy?

EP-NEC is a rare and highly aggressive malignancy with limited treatment options, particularly after multiple lines of therapy. At ESMO 2026, Leads Biolabs’ pivotal Phase IIb study of opamtistomig (LBL-024) in advanced EP-NEC following at least two prior systemic treatment lines has been selected as an LBA and Proffered Paper presentation. Opamtistomig is a bispecific antibody targeting PD-L1 and 4-1BB, designed to combine immune checkpoint inhibition with T-cell costimulation. The pivotal monotherapy study’s data supported the company’s New Drug Application submission to China’s National Medical Products Administration.

In addition to the pivotal study, “opamtistomig plus chemotherapy as first-line treatment for advanced EP-NEC: A Phase Ib/II study evaluating the combination in previously untreated advanced disease” has been selected for Proffered Paper presentations at ESMO 2026:

Neuroendocrine Carcinomas: Assessing the Durability of DLL3-Targeted Therapy

Poster 3815P presents long-term Phase I results for IDE849 (SHR-4849), a DLL3-targeted ADC carrying a topoisomerase I inhibitor payload, in relapsed SCLC and other neuroendocrine carcinomas. Longer follow-up will help clarify response durability, safety, and survival trends beyond initial activity. IDEAYA plans to initiate its first registrational trial by year-end, while Hengrui leads development in China. However, Phase I findings remain preliminary and require confirmation in later-stage trials.

Evidence from Earlier in 2026: Signals Beyond October

The ESMO Sarcoma and Rare Cancers Congress (Lugano, 12–14 March 2026) offers additional context, distinct from the October Congress presentations. Long-term ReNeu data showed durable responses to mirdametinib in NF1-associated plexiform neurofibromas, including deep responses in 18 adults and 19 children. The final four-year LANCE analysis (abstract 279MO) reported a sustained survival plateau with fixed-duration chemo-immunotherapy in metastatic large-cell neuroendocrine carcinoma, although the small prospective study requires independent validation. The congress also highlighted the ARCAGEN study on molecular profiling and treatment access in rare cancers, alongside the STARKAP trial of dostarlimab in HIV-associated Kaposi sarcoma.

Where Could the Next Breakthrough Come From?

The opportunity lies in matching biologically defined targets to clearly selected patient populations, from PKC inhibition in uveal melanoma to B7-H3- and DLL3-directed therapies. Translating these signals into practice will require mature efficacy data, randomized comparisons where feasible, and safety profiles suitable for often heavily pretreated patients. Equally important, molecular testing must translate into access to matched therapies. International collaboration and trial designs adapted to small patient populations will be essential to establish meaningful benefits in rare cancers.

Conclusion: The breakthrough may be a new way to treat rare cancers

The emerging pipeline for rare and difficult-to-treat cancers reflects a shift towards more biologically informed treatment strategies, from PKC inhibition in uveal melanoma to B7-H3- and DLL3-targeted ADCs and PD-1/VEGF bispecific antibodies. These approaches offer opportunities to address mechanisms that conventional therapies may not adequately target. However, promising response rates and early efficacy signals are only the starting point; their clinical value will depend on the durability of benefit, survival outcomes, manageable toxicity, and the identification of patients most likely to respond.

The central challenge is translating scientific innovation into reliable, accessible treatment options. This is particularly important in rare cancers, where small patient populations, molecular heterogeneity and limited opportunities for large randomized trials can slow development and complicate evidence generation. Biomarker-driven enrollment, international collaboration and trial designs tailored to these diseases will be essential to distinguish meaningful advances from preliminary signals.

ESMO 2026 will therefore be an important opportunity to assess not only which emerging therapies show promise, but also which programmes are generating the evidence needed to change clinical practice. Ultimately, the next breakthrough may not be defined by a single first-in-class drug, but by the ability to connect the right target, the right patient and a demonstrable, durable clinical benefit—bringing more effective treatment options to patients whose needs have long remained unmet.