Moving Beyond the Plateau in Immune Checkpoint Inhibition—The Imperative of Early Referral and Precision Strategies

The trajectory of immune checkpoint inhibitors (ICIs) over the past decade has been transformative, reshaping the therapeutic landscape across multiple malignancies. However, as highlighted in the new comprehensive Position Paper by Hajjar et al[1] published in the Journal of Immunotherapy and Precision Oncology (JIPO), the field now faces a plateau characterized by immune-related toxicity, therapeutic resistance, and insufficient predictive biomarkers. This apparent plateau should not be viewed as stagnation but rather as an inflection point requiring a recalibration of strategy—most notably, a shift toward earlier intervention with approved immunotherapies as well as with clinical trials, including phase 1 studies,[2–5] and biologically informed patient selection and precision immuno-oncology approaches.

A central concept that warrants stronger emphasis is the importance of timing. ICIs are frequently deployed in advanced or refractory disease, often after multiple prior therapies have altered both tumor biology and host immune function. This sequencing may inherently limit therapeutic efficacy. Increasing evidence suggests that earlier use of immunotherapy—when tumor burden is lower and immune competence more intact—can significantly enhance outcomes.[2–5] For instance, the studies by Cercek and colleagues as well as LaPelusa et al[3–5] provide a compelling illustration of this principle. In patients with mismatch repair–deficient rectal and other cancers treated with neoadjuvant PD-1 blockade, clinical complete response rates are over 90%, with many patients avoiding chemoradiation and surgery altogether;[3–5] moreover, remissions were durable. These findings highlight the potential of early immunologic intervention to achieve profound and lasting responses, particularly in biologically favorable contexts.

The concept of early immunotherapy parallels lessons from the chronic myeloid leukemia (CML) model. Early intervention with biomarker-matched targeted therapy in CML (i.e., Bcr-Abl kinase inhibitors targeting the aberrant Bcr-Abl kinase) leads to deep and near-universal molecular remissions, transforming a once lethal malignancy into one with a near-normal life expectancy.[6–8] Importantly, waiting until later stages of CML, rather than treating at diagnosis, results in low response rates and almost negligible survival impact. Although mechanistically distinct from immunotherapy-responsive tumors, the CML paradigm underscores the importance of early disease interception, when there is limited clonal heterogeneity. In the case of immunotherapy, early intervention coincides with a time when immune surveillance is preserved better than after cytotoxic chemotherapy. Applying these principles to solid tumors suggests that earlier referral for immunotherapy, especially in the neoadjuvant setting, may dramatically improve both response rates and durability.

Despite these insights, many patients are still referred for immunotherapy late in their disease course. Delayed referral not only reduces the likelihood of response but may also increase toxicity risk, as heavily pretreated patients often have compromised organ reserve and dysregulated immune systems. Early referral to specialized immunotherapy or precision oncology programs, including those with a robust clinical trial portfolio, enables optimal sequencing, comprehensive biomarker evaluation, and proactive toxicity management.

Toxicity, particularly immune-related adverse events (irAEs), remains a major barrier to maximizing the clinical benefit of ICIs. As described by Hajjer and colleagues,[1] irAEs can affect multiple organ systems and frequently necessitate treatment interruption or discontinuation.[9–12] Historically, management has relied heavily on systemic corticosteroids, which may attenuate antitumor immune responses. Emerging evidence suggests that both baseline steroid exposure and high-dose steroid use are associated with inferior outcomes.[12–16] In response, the field is shifting toward phenotype-driven and steroid-sparing strategies, particularly for dermatologic, gastrointestinal, and endocrine toxicities. These approaches aim to control toxicity while preserving antitumor immunity. Some groups have also shown that ultra-low doses of immunotherapy are effective and have significantly less toxicity.[17] Finally, not all adverse events imply a worse outcome. Othus and colleagues[18] examined patients treated in the large NCI/SWOG DART study (nivolumab and ipilimumab for rare cancers) and showed that, while grade 3–4 immune-related adverse events were associated with shorter overall survival, grade 1–2 dermatologic toxicity correlated with improved survival. A more refined understanding of immune activation—distinguishing productive antitumor responses from deleterious autoimmunity—is needed to guide therapeutic decision-making.

As pointed out by Hajjar and colleagues,[1] resistance to ICIs—both primary and acquired—represents another major challenge. Moreover, evaluating response is complicated because of pseudoprogression, including delayed pseudoprogression (both of which manifest as enlarged tumors on scans, but enlargement is due to immune infiltrates and is followed by a later response), and accelerated progression (also known as hyperprogression), the mechanism of which is unknown.[19–21] Tumor-intrinsic mechanisms, such as impaired antigen presentation and interferon signaling defects, as well as tumor-extrinsic factors, including an immunosuppressive microenvironment, contribute to therapeutic failure.[22] Moreover, other factors may be involved in resistance, including but not limited to the upregulation of checkpoints other than programmed cell death-1 (PD-1), programmed cell death ligand (PD-L1), cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), or lymphocyte activation gene-3 (LAG-3) (the only checkpoints with cognate inhibitors that are FDA-approved), inability of major histocompatibility complex (MHC) to present the aberrant tumor-associated neoantigens, silencing of mutations at the transcription level, and an inadequate T-cell repertoire.[22,23] Increasingly, it is recognized that resistance is multifactorial and dynamic, requiring integrated approaches for effective characterization and intervention.

Importantly, biomarker development has lagged behind clinical need. PD-L1 expression and tumor mutational burden (TMB) are important but imperfect biomarkers.[24–26] Some studies suggest that PD-1 on tumor-infiltrating lymphocytes is more predictive of ICI response than PD-L1 (both performed by immunohistochemistry).[27] These inconsistencies reflect both biological heterogeneity and technical limitations. Unique biomarkers such as autoantibodies may also prove important.[28] Some groups have proposed composite biomarker strategies integrating genomic, transcriptomic, and immune profiling data, both from tissue and blood, which may provide more robust predictive power.[29] Artificial intelligence and machine learning approaches may further enhance biomarker development by enabling the integration of complex, high-dimensional datasets. These tools hold promise for improving patient selection but require rigorous prospective validation.

The microbiome has emerged as another important determinant of both response and toxicity. Studies have demonstrated that gut microbial composition can influence ICI efficacy and the development of immune-related adverse events.[30,31] These findings open the door to novel therapeutic strategies, including microbiome modulation, though clinical application remains in early stages.

Combination therapies represent a promising avenue for overcoming resistance but can be associated with increased toxicity. Rational combinations based on mechanistic insights—rather than empirical approaches—are essential to balance efficacy and safety.[32] Lowering doses of targeted therapy has not been found to compromise efficacy,[32] and ultra-low doses of ICIs have also shown efficacy.[17] Biomarker-driven trial designs will be critical in identifying optimal combinations.

Cost and access considerations further complicate the landscape. ICIs are associated with substantial financial burden, and their widespread use raises concerns about sustainability. Precision approaches that improve patient selection and minimize unnecessary treatment may enhance cost-effectiveness.

Given this background, early referral emerges as a unifying strategy to address many of the challenges. Patients evaluated earlier in their disease course are more likely to benefit from immunotherapy and experience fewer severe toxicities; these patients should also be allowed greater access to clinical trials. Early engagement also facilitates comprehensive biomarker assessment and multidisciplinary care. Operationalizing early referral will require coordinated efforts, including physician education, streamlined referral pathways, and increased access to specialized centers. Clinical trials should increasingly focus on earlier disease settings and incorporate translational end points to better understand mechanisms of response and resistance.

Precision immuno-oncology, including the development of biomarker-driven treatment frameworks and the characterization of resistance mechanisms, is advancing quickly. These efforts underscore the importance of integrating clinical and translational research to move the field forward.

In conclusion, the transition from promise to plateau in ICI therapy reflects both the success of immunotherapy and the limitations of current approaches. The next phase of progress will depend on embracing precision strategies, prioritizing early intervention, and applying lessons from successful disease models such as mismatch repair–deficient solid cancers targeted with ICIs in the neoadjuvant setting, and CML whose hallmark aberrant Bcr-Abl kinase is most successfully targeted at first diagnosis. Both models serve as poster children for the transformative rather than incremental impact of biomarker-matching and treatment at diagnosis rather than later. By shifting toward earlier, biology-driven treatment, the field can move beyond the current plateau and realize the full potential of immuno-oncology.