PSI perspectives from the largest oncology congress in Europe
At this year’s European Society for Medical Oncology (ESMO) Congress (held between 17 and 21 October in Berlin, Germany), several members of PSI’s oncology team were in attendance. Read on for their takeaways from the presented research and what this means for our sponsors and their clinical trials.
ESMO 2025 was a truly global event, with over 200 sessions featuring more than 650 speakers from around the world, who presented their groundbreaking research to 37,000 attendees. Choosing from the many highlights, precision oncology, novel therapies in the context of antibody-drug conjugates (ADCs), dose optimization, and the interpretation of study design regarding biological sex are all factors that impact (or have the potential to impact) the timely delivery of pivotal oncology trials in 2026 and beyond.
Precision oncology advances
Adoptive cell therapies
2024 was a breakthrough year for adoptive cell therapies in solid tumors, with the approval of two new therapies: a tumor-infiltrating lymphocyte (TIL) T-cell therapy for metastatic melanoma and an autologous T-cell receptor (TCR) therapy for refractory advanced synovial sarcoma. Adoptive therapies, which use the patient’s cells to create a personalized treatment, formed a significant part of precision oncology discussions at ESMO in 2025.
There are two main adoptive cellular therapy platforms to treat solid tumors:
- TIL: A platform using resected tumor material and the T cells already present within the tumor
- TCR or CAR: A platform using T cells from peripheral blood and modifying them so they recognize cancer antigens
Challenges with adoptive cell therapies highlighted at ESMO included:
- Identifying new and specific antigen targets for improved efficacy and safety: Better antigen selection can improve toxicity profiles, and the CAR’s affinity to the target is also important. Low-affinity variants of target antigens could also prove safer while maintaining the same anti-cancer efficacy. Preclinical studies show some discrimination between normal and high (i.e., cancerous) expression of the target antigen
- Improving T-cell fitness: Upon chronic antigen stimulation, T cells become exhausted and dysfunctional. Due to this phenomenon, despite initial response, tumors eventually relapse if they are not cleared on time. Several genes have been identified that could potentially be knocked out to increase T-cell fitness. There is still a long way to go; however, the first models look promising
- Preventing tumor escape: The loss or downregulation of antigen expression and/or the immune-suppressive tumor microenvironment must be overcome. Options include targeting two antigens simultaneously by co-administering different CAR-T products, having two CARs on a single T cell, or constructing CAR-Ts with two antigen-binding sites on a single extracellular domain
We anticipate substantial investment in research and development to address these emerging challenges with T-cell therapies. Beyond this, the next few years will be shaped by addressing manufacturing and supply chain issues, regulatory (and reimbursement) expectations, and efficacy in multiple types of cancer.
Adoptive cell therapies are complex and expensive; however, recent advances and global adoption have helped improve patient access and manufacturing capacity, thus making them more economically viable for sponsors.
Tumor-agnostic therapies
For the first time in ESMO’s history, tumor-agnostic therapies were on a separate conference track. Moving from understanding cancer by location or origin to thinking of cancer by biomarker expression has been a significant step forward since 2017 [1, 2]. Presenters shared several insights related to challenges and opportunities within the current landscape, including:
- Approving drugs by indication delays patient access to effective drugs: Molecular profiling of tumor and associated immune cells is needed in the era of precision oncology to guide therapy and regimen choice; eight drugs have been approved by the FDA for tissue-agnostic treatment, with more expected in the coming years [3]
- Response to treatment may be shaped by the tumor: Approval of a tumor-agnostic therapy doesn’t mean that all cancers with the antigen will respond to the therapy. Response is shaped by the location of the tumor, among other factors, needing close scrutiny of tumor-agnostic therapy efficacy and safety [4]
- There are real-world implementation hurdles: Real-world availability of tumor-agnostic treatments limits both research (especially across medical systems divided into “breast cancer wards,” “lung cancer wards,” and so on) and patient access. Reimbursement is often inconsistent (which we observe across many therapeutic areas). Next-generation sequencing must become a standard of care to ensure that the right treatments reach the right patients
Traditional randomized controlled trials are often unfeasible in tumor-agnostic settings. Single-arm trials poorly control for true false positive rates and provide little overall information on how to make informed clinical decisions. The use of external control arms with high-quality data is one option for building a more robust design; however, these are often challenged by regulators [5].
The ESMO Tumor-Agnostic Classifier and Screener (ETAC-S), published here, proposes minimum requirements for screening tumor-agnostic potential and provides a framework to accelerate drug development as a stepwise process with recommended trial designs.
With the rise of tumor-agnostic therapies, sponsors of new oncology therapies have an opportunity to broaden their horizons and contribute to the momentum of the shift toward biomarker-based disease definitions for diagnosis and treatment.
Tumor-agnostic studies mean that patients with the misfortune to develop cancer in a body region not covered by a helpful drug’s approval now have the opportunity for treatment. Ensuring the approval of tumor-agnostic therapies through adhering to ESMO guidance and smart trial design means that many, many patients sharing the same misfortune can have the opportunity of life.
ADCs: Using technology to improve efficacy
Despite being one of the most successful developments in oncology over the past few years, current high-impact issues with ADCs include (sometimes unpredictable) toxicity, target selection, regulator-driven challenges [6], and unclear optimal dosing (discussed further later) [7]. ADCs were discussed extensively at ESMO, emphasizing the fact that we can improve the next generation of these therapies with the technologies available now, including:
- Targeting the tumor microenvironment
- While recognized as scientifically valid, targeting the tumor microenvironment has long been a challenge that clinicians have sought to address. Advances presented from early-phase clinical trials suggest positive results not only in killing tumor cells themselves but also in killing cells in the microenvironment that nourish the tumor
- This is a potentially game-changing innovation – thinking beyond monotherapy, tumor microenvironment-targeting therapies in combination with cytotoxics or targeted therapies could help overcome the challenges of breaking through the fibrotic tumor structure and delivering treatment to patients (for example, in pancreatic cancer, where clinicians worry about treatment actually reaching the cancerous cells)
- Non-internalizing targets
- Competition for antigens/proteins is fierce – over 20 TROP2-targeting agents and more than 30 HER2-targeting agents are in development; perhaps all internalized targets have been identified. Selecting a non-internalizing, tumor-associated antigen provides a novel approach that can differentiate the population of patients who can be treated
- Novel payloads
- When acquired multidrug resistance occurs, resulting in patients becoming resistant to a whole drug class, going further than using antimicrotubule or topoisomerase I inhibitors is the next step
- Inhibiting protein translation or trafficking is a promising approach; cells lack a mechanism to counteract this. However, this potent approach is also toxic to healthy cells, so specificity is needed. Preclinical studies are ongoing and encouraging
- Turning drugs into regimens
- Combining ADCs with other drug classes may deepen and prolong therapeutic benefit. ADC/CPI combinations have transformed the treatment of bladder cancer, and several late-phase trials are ongoing in other indications. Other ADC partners (including targeted therapies, cell therapies, and bispecific antibodies) are also under evaluation to explore potential synergies
- Careful consideration – such as that given to many current cytotoxic regimens – of non-overlapping mechanisms of action and non-overlapping toxicities is needed. Phase 1 and 2 trials combining ADCs with drugs targeting other pathways (e.g., DNA damage response pathways) are in development. Findings from preclinical studies on multiple payload ADCs could represent a future direction. Carefully understanding dosing (could a lower-than-monotherapy dose be given to complement the cytotoxic?) and scheduling to mitigate toxicity is key.
Finding the right patients for new ADC trials could require more comprehensive genetic testing, thereby restricting patient pools (and increasing screen failure rates) but potentially improving response rates.
We are seeing a wave of better-designed ADCs (amongst other types of antibodies), with higher specificity and improved efficacy and safety. As the pipelines are expanding, we are experiencing more competition for antigen-defined cohorts, and enrollment is becoming more competitive.
Dose optimization
Project Optimus is an initiative designed to reform dose optimization in oncological drug development. The traditional approach faces several challenges:
- In the past, dose selection in registrational trials has been guided by the maximum tolerated dose (MTD) or maximum administered dose (MAD) captured by early dose-finding studies
- This can result in a recommended dosage in the labeling that may be unnecessarily high (which could be acceptable for cytotoxics but not appropriate for targeted therapies) and is poorly or not adequately tolerated, affecting the patient’s ability to remain on the drug (and their quality of life) and thereby ability to derive maximal clinical benefit
- Patients who experience adverse reactions may have difficulty tolerating subsequent treatments, especially if the treatments are associated with similar toxicities or if resistance has developed
Project Optimus can have significant implications for your oncology trials. If questions arise at the time of approval regarding whether the approved doses or schedules are optimal, the FDA can use its authority to require sponsors to conduct additional dose optimization by issuing postmarketing requirements. Between 1 January 2012, and 31 December 2022, 132 novel oncology drugs were approved by the FDA, and 376 postmarketing requirements were issued – 44% of which collected additional dosing information for 59% of the 132 approved drugs [8].
In Phase 1 studies, a model-based escalation and multiple expansion cohorts are recommended for PK/PD and efficacy. Randomized multiple doses and interim analyses in Phase 2 studies should inform Phase 3 studies, where dosing is justified by exposure-response and prior data. Postmarketing dose optimization is also advised.
The discussions held at ESMO underscore the need to adhere to the FDA’s new requirements, ensuring that life-changing treatments can proceed smoothly to approval.
We’ve already started seeing these changes in dose optimization as parts of our study protocols, including requiring adaptive elements in ADC trials. Understanding the impact of these changes is vital to make sure clinical trial data is relevant, and our sponsors don’t need to conduct additional studies post-approval.
Sex differences in the design, analysis, and interpretation of oncology clinical trials
Biological sex can influence disease incidence, progression, and response to treatment [9, 10], as well as pharmacodynamic and pharmacokinetic profiles [11]. The FDA’s 2025 guidance, “Study of Sex Differences in the Clinical Evaluation of Medical Products”, is designed specifically for clinical trials and was covered in depth at ESMO. Not recognizing these differences can result in suboptimal dosing strategies, increase the risk of unforeseen AEs, and also miss opportunities for biological sex-specific treatment options.
For example, biologics that stimulate immune function have greater efficacy in females, while biologics that repress immune function have greater efficacy in males. Discounting reproductive cancers, an analysis of AEs by sex in patients treated between 1980 and 2019 determined females have a 34% higher risk of severe AEs, including a 49% increase in risk among those receiving immunotherapy [12]. Severe hematologic AEs were also more frequent in females than males [12]. However, to date, no biological sex-specific treatment or treatment schedules have been considered.
Considerations for oncology clinical trial design, analysis, and interpretation
- When designing a clinical trial, consider whether the research questions and assumptions are appropriate for both biological sexes
- Evaluate if sex-specific dosing could enhance treatment efficacy or reduce toxicity for either males or females
- Even in the absence of prior evidence of sex differences, report and analyze outcomes separately for males and females to identify any potential disparities that may exist
- Conduct interaction tests to formally assess sex differences and pursue further research on such differences if suggested
- Males and females should be viewed as biologically distinct groups rather than just subgroups, emphasizing the importance of sex-specific analysis.
- Any observed differences in treatment efficacy should not be dismissed as mere statistical errors; instead, they may reflect genuine biological differences or drug effects
- When differences in toxicity are observed, it’s important to explore whether dose adjustments for sex could optimize the benefit-risk balance
We expect that more significance will be given to balancing biological sex in enrolling oncology trials, and stratification of efficacy, safety, and PK/PD data by biological sex will become standard in Clinical Study Reports, ensuring that regulatory bodies have all the necessary information to approve new therapies.
The FDA’s guidance reminds us that our patients are not statistics. From enrollment planning to data management, we must proactively balance recruitment to ensure our analyses are structured to capture meaningful differences.
In summary
These are just a few of the findings contributing to the evolving trends in oncology drug development at ESMO 2025. This year’s meeting centered on truly radical precision medicine developments, as well as how we, as a community, must perceive cancer. As PSI’s oncology specialists highlight, cancer does not follow rules – forward-thinking perspectives and collaborative problem-solving, alongside careful feasibility, are needed to ensure clinical trials can be run effectively.
Learn more about PSI's oncology pivotal trial solutions today
As the complexity of the oncology clinical trial landscape grows, so does the importance of having an experienced, dedicated guide by your side.
Abbreviations
ADC, Antibody-Drug Conjugate;
AE, Adverse Event;
CAR, Chimeric Antigen Receptor;
CPI, Checkpoint Inhibitor;
ESMO, European Society of Medical Oncology;
FDA, Food and Drug Administration;
HER2, Human Epidermal Growth Factor Receptor 2;
MTD, Maximum Tolerated Dose;
PD, Pharmacodynamics;
PK, Pharmacokinetics;
TCR, T-Cell Receptor;
TIL, Tumor Infiltrating Lymphocyte;
TROP2, Tumor-Associated Calcium Signal Transducer;
References
1. Hanahan, D., Hallmarks of Cancer: New Dimensions. Cancer Discov, 2022. 12(1): p. 31–46.
2. Subbiah, V., et al., The evolving landscape of tissue-agnostic therapies in precision oncology. CA Cancer J Clin, 2024. 74(5): p. 433–452.
3. André, F., et al., Forget lung, breast or prostate cancer: why tumour naming needs to change. Nature, 2024. 626(7997): p. 26–29.
4. Sledge, G.W., et al., Real-world evidence provides clinical insights into tissue-agnostic therapeutic approvals. Nature Communications, 2025. 16(1): p. 2646.
5. Monnereau, M., et al., Acceptance of external control arms by HTA agencies: a review of oncology submissions in France, England, Germany and Norway from 2021 to 2023. Br J Cancer, 2025.
6. Crescioli, S., et al., Antibodies to watch in 2025. MAbs, 2025. 17(1): p. 2443538.
7. Buyukgolcigezli, I., A.K. Tenekeci, and I.H. Sahin, Opportunities and Challenges in Antibody-Drug Conjugates for Cancer Therapy: A New Era for Cancer Treatment. Cancers (Basel), 2025. 17(6).
8. Collins, G., et al., An Analysis of Dosing-Related Postmarketing Requirements for Novel Oncology Drugs Approved by the U.S. Food and Drug Administration, 2012-2022. Clin Cancer Res, 2024. 30(5): p. 937–941.
9. Rubin, J.B., The spectrum of sex differences in cancer. Trends Cancer, 2022. 8(4): p. 303–315.
10. Bernardez, B., et al., Sex and gender differences in cancer pathogenesis and pharmacology. Clin Transl Oncol, 2025. 27(10): p. 3837–3848.
11. Lucena, M.I., et al., Sex/gender differences in clinical pharmacology: A perspective from the IUPHAR World Smart Medication Day 2025. Pharmacol Res, 2025. 219: p. 107889.
12. Unger, J.M., et al., Sex Differences in Risk of Severe Adverse Events in Patients Receiving Immunotherapy, Targeted Therapy, or Chemotherapy in Cancer Clinical Trials. J Clin Oncol, 2022. 40(13): p. 1474–1486.
