Refining and re-defining standard of care

This is the final installment of our ESMO series from Madrid, one of the most informative and important gatherings in global oncology. Across the first three parts, we shared what we heard in the sessions and in the corridors. The shared takeaway is that the question has moved beyond “does it work?” to “where does it belong, for whom, and can patients get it?”

In this last piece, we look ahead to what comes next. To catch up on earlier findings access here:

Executive summary: Part 4 looks at where oncology is heading, from new modalities of treatment to new models of evidence generation.

Below, our experts cover three themes:

  • Radiopharmaceuticals and novel targets: Radiopharmaceuticals and the wave of new therapies directed at novel epitopes and targets.
  • Next-generation immunotherapies: Immunotherapies that work differently from immune checkpoint inhibitors and aim for more precise control of the immune response.
  • Conclusion: ESMO meeting themes and takeaways revisited. Learn about Lumanity’s work elevating alternative endpoints, multidisciplinary teams, and real-world evidence.

Radiopharmaceutical Innovation Needs Evidence and Delivery Infrastructure to Translate into Commercial Success

Graeme Hacking, PhD(Cantab), LRAM, DipRAM, FRSPH, VP, Medical Affairs Consulting

ESMO 2026 highlighted a radiopharmaceutical sector increasingly focused on treatment after lutetium-177, alternative tumour targets and the biology of resistance. For pharmaceutical companies, the commercial opportunity depends on establishing where each therapy belongs within the treatment pathway. Encouraging response rates can support investment, but meaningful differentiation will require evidence of durable benefit, acceptable cumulative toxicity and dependable delivery.

Early alpha-therapy findings illustrated both the promise and the uncertainty. TheraPb evaluated the PSMA-directed lead-212 agent ADVC001 in 22 patients. At the recommended phase 2 doses, the reported PSA50 response rate was 80% and median radiographic progression-free survival was 11.2 months. All five patients with RECIST-evaluable disease responded. That small denominator remains essential when interpreting the results; this uncontrolled study cannot establish superiority over existing therapies.

ProTACT addressed activity after lutetium exposure. At evaluated dose levels, actinium-225 PSMA agent FL-020 produced PSA50 responses in nine of nine lutetium-naive patients and six of eight previously exposed patients. These findings support further investigation of a potentially important sequencing opportunity. However, small subgroups and a PSA-based endpoint leave response durability and comparative clinical benefit unresolved. Companies pursuing this population will need prospective evidence that defines which patients benefit.

An alpha program pursuing treatment after lutetium will require a different comparator and evidence package from one seeking earlier use. This makes commercial positioning an early development decision, with trial design shaped by the population and clinical role the company intends.

Lead-212 also generated interest in neuroendocrine tumors. VMT-α-NET reported objective response rates, including unconfirmed responses, of 33% and 50% in two cohorts. Estimated progression-free survival at 18 months was 72% across 68 patients. Participants had received no previous radiopharmaceutical therapy, so these data cannot answer whether treatment works after earlier peptide receptor radionuclide therapy. No dose-limiting toxicities (DLTs), Grade 4 or 5 treatment-emergent adverse events (TEAEs), or adverse event-related treatment discontinuations were reported. Continued renal safety assessment will also be important.

Sequencing may become more complex as retreatment develops. Re-LuPSMA reported interim safety findings in 20 patients selected for previous response to lutetium-PSMA. Two possibly treatment-related serious anaemia events remained below the protocol stopping threshold; efficacy results were unavailable. For developers of subsequent therapies, selected patients receiving further lutetium could become a relevant comparator. Evidence generation must therefore anticipate how clinical practice may evolve.

Resistance biology strengthens the rationale for looking beyond PSMA. Exploratory studies found declining plasma-predicted PSMA expression at progression in 11 of 17 paired samples. Although this does not validate a treatment-selection assay, it supports investigating target reassessment. BActinium-1, targeting B7-H3, and ATNM-400, targeting HER3, illustrate alternative development strategies. Both were trials in progress, offering no clinical efficacy conclusions. Their potential commercial relevance lies in reaching patients poorly served by further PSMA-directed therapy.

These programs create opportunities for partnerships connecting target biology, therapeutic development and imaging. Imaging and biomarker research could help identify suitable patients and guide switching between targets. Investment decisions must nevertheless remain specific to each construct, including tumor retention, normal-tissue exposure and therapeutic window.

These programs create opportunities for partnerships connecting target biology, therapeutic development and imaging

Intraperitoneal radium-224 in ovarian cancer illustrates another expansion route: regional treatment of residual disease after surgery, subject to future efficacy evidence and practical integration.

Patient experience will also influence adoption. CCTG PR21 reported generally maintained quality of life with lutetium-PSMA compared with deterioration during docetaxel treatment. Such findings strengthen the case for collecting patient-reported outcomes alongside comparative efficacy and healthcare resource use. For payers and clinicians, value will depend on the overall treatment experience and outcomes achieved, making these measures commercially relevant throughout development.

Takeaways

Delivery capability must advance alongside clinical evidence. Isotope availability, manufacturing release, transport and treatment appointments must work together reliably. Partnerships with isotope suppliers, radiopharmacies and treatment centers can therefore contribute directly to commercial viability. Companies should assess whether the proposed regimen can be supplied consistently across intended markets and accommodated within available clinical capacity.

Medical Affairs should help connect these requirements through integrated evidence generation planning. Priorities include dose optimization, long-term safety, sequencing, patient selection and service capacity, with disease-specific questions addressed across indications. ESMO 2026 supports a broader radiopharmaceutical future, but commercial success will depend on resolving these practical and clinical uncertainties. Companies that define a specific unmet need, demonstrate meaningful benefit and establish a dependable route to treatment will be better positioned to translate early promise into sustained adoption.

Beyond Checkpoint Blockade: New Modalities for Taking Control of Immune Responses

Jeff Bockman, PhD, EVP, and Dennis Chang, PhD, SVP, Strategy Consulting

For years now, PD-(L)1 immune checkpoint blockade has dominated the immuno-oncology conversation. Even today, the “hottest” new class is based on the same backbone, the PD-(L)1×VEGF bispecifics. And in fairness, many other IO drug classes have risen to prominence over the years only to fail. But at ESMO 2026, we may be seeing a shift in immuno-oncology, with promising readouts across a diverse set of novel immunotherapy modalities.

Personalized neoantigen mRNA vaccine: A phase 3 trial of Merck/Moderna’s personalized neoantigen vaccine intismeran autogene was featured in the first Presidential Symposium of the conference, as an add-on to standard pembro for adjuvant treatment of melanoma. The vaccine combination significantly improved both relapse-free survival (RFS) and distant metastasis-free survival (DMFS) with hazard ratios ~0.6. Although this was not as impressive as the phase 2 data, it was still a definitive win, and with minimal added toxicity. The first personalized mRNA therapeutic vaccine for oncology will soon be approved and redefine the standard of care.

In-situ vaccination: Syncromune’s SYNC-T is a drug-device platform that relies on partial cryolysis of a target lesion to liberate patient-specific tumor neoantigens directly into the microenvironment. This is immediately followed by the intratumoral infusion of SV-102—a fixed-dose multi-target immunomodulator combining anti-PD-1, anti-CTLA-4, a CD40 agonist, and a CpG-ODN adjuvant. The intratumoral infusion also pushes the antigens and immunomodulators into the lymphatic system for increased immune cell access, following a biologic and immunologic rationale for local delivery of IO therapies that has been such an anathema to most large pharma.

The phase 1 trial of SYNC-T SV-102 showcased at ESMO focused on metastatic prostate cancer, a tumor type historically viewed as an immune desert. With 29.6 months of median follow-up, the trial confirmed durable systemic clinical responses well beyond the initial lesion site. Although the sample size was small, the 24-month OS was impressive at 80%: 70% for castration-resistant prostate cancer (mCRPC; n=10) and 100% for hormone-sensitive prostate cancer (mHSPC; n=5). Importantly, the localized delivery of this multi agent cocktail averted the high-grade systemic toxicities (typically 42–53%) observed with systemic multi-checkpoint doublets: SYNC-T SV-102’s grade 3-4 irAE rate was 0%.

Selective T cell activation: Marengo’s invikafusp alfa utilizes cooperative dual-binding to selectively target and expand Vβ6/Vβ10 T-cells—specific lineages heavily implicated in tumor infiltration—without altering other immune cell balances. Current immune checkpoint inhibitors (ICIs) are frequently limited by indiscriminate T-cell activation, where anti-tumor activity may come with severe immune-related adverse events. The first-in-human data for invikafusp presented at ESMO 2026 provided a meaningful clinical proof-of-concept for avoiding this pitfall.

In a heavily pretreated cohort of advanced solid tumors resistant to multiple lines of therapy, the agent yielded a 59.3% DCR and a 15% ORR at optimal doses. Crucially, it selectively drove both circulating and intratumoral expansion of the target T-cells with a highly tolerable safety profile, validating the mechanistic principle while opening the opportunity for immunotherapy combination.

4-1BB-based T-cell engager: Bispecific T-cell engagers (TCEs) are not new—the first (Blincyto) was FDA-approved in 2014—but thus far all approved TCEs have used CD3 as the T-cell target. In contrast, BeOne’s BGB-233 (or BGB-B2033) is a GPC3 × 4-1BB bispecific antibody. The costimulatory molecule 4-1BB is a highly potent mediator for CD8+ T-cell activation, but historical systemic agonists like urelumab had to be discontinued due to severe hepatotoxicity. BGB-233 solves this through structural strictness: it triggers 4-1BB signaling only upon cross-linking with GPC3 on the surface of tumor cells. Presenting early phase 1 data in hepatocellular carcinoma (HCC), where GPC3 is overexpressed in roughly 90% of cases, the molecule delivered marked CD8+ activation localized to the tumor landscape, with a rate of grade 3+ AEs of only 5%. The ORR at the recommended phase 3 dose was nearly 36%, in an HCC population where more than 90% of patients had previously been treated with a PD-(L)1 inhibitor. This TCE not only decoupled the anti-tumor potential of 4-1BB from its historical safety liabilities, but also could overcome at least a subset of ICI resistance mechanisms.

Takeaways

The overarching theme of the next wave of immunotherapy is spatial and biological control. As showcased at ESMO 2026, various platforms may achieve tighter control of immune response, whether by restricting activation to a precise subset of tumor-reactive T-cells, engineering strict tumor-antigen dependency for costimulators, or using local delivery to modulate the TME. The lesson from Madrid amplifies what many in the IO space have believed and shown in models: that to overcome checkpoint resistance and mitigate immune toxicity, cancer immunotherapies must move past the standard systemic, global immune activation in favor of more localized precision.

Relevant trial and reference notes

  • 2253P: 212Pb-ADVC001 (AdvanCell) updated results from phase 1 TheraPb trial in PSMA-positive metastatic castration-resistant prostate cancer (mCRPC)
  • 2323eP: 225Ac-FL-020 (Full-Life Technologies), targeting PSMA, in phase 1 ProTACT study in mCRPC
  • 2396RO: 212PbVMT-α-NET (Perspective Therapeutics) in a phase 1/2 trial in advanced SSTR2+ neuroendocrine tumors (NETs)
  • 2246P: 177Lu-PSMA-617 (Pluvicto; Novartis) interim safety analysis from phase 2 RE-LuPSMA trial of retreatment in mCRPC
  • 8727P: 177Lu-PSMA-617 (Pluvicto; Novartis) plasma epigenomic profiling study in mCRPC
  • 2390eTiP: 225Ac-AKY-2519 (Aktis Oncology), targeting B7-H3, in phase 1b BActinium-1 study for mCRPC
  • 2386eTiP: ATNM 400 (Actinium Pharmaceuticals) in phase 1 study for mCRPC
  • 1446eTiP: Intraperitoneal α-emitting Radium-224 in a phase 2 trial for homologous recombination proficient primary advanced epithelial ovarian cancer
  • 2210RO: ¹⁷⁷Lu-PSMA-617 (Pluvicto; Novartis) versus docetaxel in CCTG PR21 study; patient-reported quality of life in mCRPC
  • LBA1: Intismeran autogene (Merck/Moderna) + pembrolizumab in phase 3 INTerpath-001 for adjuvant treatment of melanoma
  • 2247P: SV-102 (Syncromune) in phase 1 for metastatic prostate cancer
  • 1948O: Invikafusp alfa (Marengo) in phase 2 START-001 for high tumor mutational burden (TMB-H) solid tumors
  • 1679O: BGB-B2033 (BeOne) in phase 1 for hepatocellular carcinoma (HCC)

Conclusion

ESMO 2026 delivered practice-changing pivotal readouts alongside promising early signals for emerging therapies. The congress also highlighted novel mechanisms and modalities, next-generation versions of established drug classes, and valuable lessons drawn from trial failures, biomarker analyses, and subgroup data. This series covers only a portion of the data presented, but the breadth and depth of findings were clear.

Several themes stood out:

  • Pivotal and early-stage progress: Pivotal trial results are poised to change clinical practice, and early data point to promising new therapies.
  • Innovation across modalities: Novel mechanisms and modalities are emerging. Existing drug classes are also being expanded and improved through next-generation chemistry and biologic engineering.
  • Learning from setbacks and subgroups: Trial failures, biomarker analyses, and subgroup findings offered important insights to guide patient selection and future development.

Lumanity at ESMO 2026

Lumanity co-authored several data presentations at this year’s congress:

  • 3315O (Proffered Paper):When overall survival is not enough: The emerging need for context-sensitive endpoint frameworks in oncology.
    • Lumanity co-author: Dan Gladwell
    • This presentation supports formalizing the intrinsic value of endpoints beyond overall survival (OS) in Health Technology Assessments, clinical guidelines, and other data evaluations. Lumanity continues to advance this initiative, and further updates will follow.
  • 2535P (Poster):Global quantitative chart review of multidisciplinary team (MDT) care and treatment (Tx) in patients (pts) with stage (Stg) I-II, unresected non-small-cell lung cancer (urNSCLC).
  • 3523eP (e-Poster):The Hidden Toxicity: Measuring Cancer’s Mental Health Burden in Real-World Data.
    • Lumanity co-author: Josine Kuiper
  • 4622eP (e-Poster):Real-World Treatment Utilization in Biomarker-Positive Cancer Patients: Evidence from the Dutch PHARMO Data Network.
From new modalities to new models of evidence generation. Where is oncology headed?
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These presentations reinforce a broader point: the implications of the data shared at ESMO reach well beyond scientific understanding and clinical outcomes assessment. The findings shape decisions and policies on access, health economics, quality-of-life assessment, regulatory methodology, research funding, and more. As cancer treatment grows more complex, the systems that govern its use, and those that drive the development of future therapies, must evolve and innovate with it.

To help biopharma companies adapt to this evolution across functions and over time, Lumanity remains committed to staying at the forefront of the data and the discussions surrounding it. We welcome the opportunity to connect you with our experts.

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