However, some challenges still limit its implementation in clinical practice
Randomised controlled trials (RCTs) have been instrumental in establishing immunotherapy with immune checkpoint inhibitors (ICI) as a transformative treatment for several aggressive, advanced solid cancers. These trials provided high-quality efficacy data under controlled conditions, laying the foundation for regulatory approvals and clinical guidelines. However, the stringent eligibility criteria of RCTs often exclude conditions frequently encountered in clinical practice, such as poor performance status, organ dysfunction, untreated brain metastases, or pre-existing autoimmune diseases—the latter being a specific exclusion criterion in virtually all ICI RCTs conducted so far. Additionally, patients enrolled in clinical trials are often younger and healthier than those treated in clinical practice. These limitations raise concerns about the generalisability of trial results to broader patient populations.
Studies estimate that over 50% of real-world cancer patients may not be represented in pivotal ICI trials (Eur J Cancer. 2017 Mar:74:89-95), highlighting the need for complementary data sources and initiatives to broaden the representativeness of clinical trial populations to reflect the real world. Real-world data (RWD) offer an invaluable opportunity to address these gaps by capturing treatment effectiveness and safety in routine clinical settings. Unlike RCTs, which focus on idealised populations, RWD reflect the diversity of patients seen in clinical practice, including those with comorbidities. For instance, studies leveraging RWD have demonstrated that ICIs may improve outcomes in unselected, real-world populations with certain cancers, beyond patients traditionally represented in trials (Eur J Cancer. 2017 Mar:74:89-95 ; EClinicalMedicine. 2024 Feb 12:69:102485 ; Eur J Cancer. 2021 Jul:151:115-125 ). Moreover, RWD have provided specific guidance for the treatment and monitoring of challenging patient populations, such as those with autoimmune diseases, organ transplants, or chronic infections (J Immunother Cancer. 2021 Mar;9(3):e001664), not represented in RCTs. RWD have also been critical in validating biomarkers for refining treatment selection (Eur J Cancer. 2024 Feb:198:11347 6) and in reducing lifelong drug exposure through shortened immunotherapy durations (Curr Oncol Rep. 2022 Jul;24(7):905-915). Furthermore, RWD have informed strategies for managing immune-related adverse events (irAEs), especially rare toxicities (J Immunother Cancer. 2021 Jul;9(7):e002896), where high-level evidence from RCTs is often unavailable. They also guide the management of steroid-refractory irAEs, a particularly challenging area (Eur J Cancer. 2024 May:203:114028).
Despite these successes, the integration of RWD into clinical practice and regulatory decision-making for cancer immunotherapy faces several challenges. The quality and consistency of data are critical issues, as variability in collection methods, missing information and unstructured formats can undermine reliability. A recent study found that real-world data frameworks are often deemed insufficient to inform clinical practice (Eur J Cancer. 2021 Sep:155:136-144).
Standardisation of data sources, such as electronic health records, registries, and laboratory results, is essential to minimise biases and improve comparability. To maximise the utility of RWD, robust study design is paramount. Real-world studies (RWS) should begin with a standardised protocol and pre-specification of endpoints (Am J Epidemiol. 2024 Nov 4;193(11):1625-1631), possibly aligned with those used in RCTs for comparability.
The ESMO Guidance for Reporting Oncology real-World Evidence (ESMO-GROW) offers a detailed framework for reporting RWE, emphasising transparency in study design, consistent outcome definitions, and comprehensive patient demographics. Methodological rigor can be enhanced by using innovative tools like target trial emulation, which mimics RCT design in observational studies, and propensity score methods to mitigate confounding (Clin Pharmacol Ther. 2023 Jun;113(6):1217-1222). Disseminating results through clear and reproducible reporting standards ensures the credibility of RWD and supports its integration into clinical practice. Regulatory bodies, such as the Food and Drug Administration and the European Medicines Agency, are increasingly incorporating RWD into decision-making processes for drug approvals and post-marketing surveillance (J Diabetes Sci Technol. 2019 Mar 12;14(2):345–349). Health technology assessment (HTA) agencies may leverage RWD to evaluate the real-world effectiveness and cost-effectiveness of therapies (Value in Health, Volume 26, Issue 4, 11 - 19).
By bridging the gap between RCTs and clinical practice, RWD can deliver insights that complement trial evidence. This synergy ensures that immunotherapy continues to offer durable benefits across diverse patient populations while minimising adverse events, unnecessary long treatment durations, and reducing financial costs.
