A SITC vision: adapting clinical trials to accelerate drug development in cancer immunotherapy.

Introduction

Immunotherapy (IO) is now a standard of care for many patients with cancer with early or advanced disease. Years of dedicated work provided initial proof of principle that harnessing the immune system—with cytokines, a vaccine, a cytotoxic T lymphocyte-associated protein 4 (CTLA-4)-specific antibody, or an oncolytic virus—could benefit some patients with cancer. With this foundational clinical evidence in hand, the last decade witnessed a marked acceleration of cancer IO drug approvals by the US Food and Drug Administration (FDA). To date, the most impactful drug platforms are immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR)-T cells, and T-cell engagers (TCEs). These initial cancer immunotherapies transformed cancer care due to their novel mechanisms of action, unique side effect profiles, and delivery of long-term clinical benefits to patients. However, many patients with cancer who appropriately receive IO either have cancers that fail to respond at all (primary resistance), or cancers that progress after initial benefit (secondary resistance). 1 There is clearly significant room for improvement in making treatments accessible and in identifying patients who will benefit from these therapies.

Selected approved agents provide tantalizing hints about how to further accelerate progress ( figure 1 ). Targeting distinct antigens, B cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D), extended the benefit of CAR-T or TCEs from B-cell cancers to multiple myeloma, a major unmet clinical need. 2 4 The TCE specific for glycoprotein 100/major histocompatibility complex (MHC) (tebentafusp) extended the utility of TCEs from B-cell cancers to solid tumors (uveal melanoma), and from a simple protein to a more complex drug target (antigen to MHC/antigen) on the tumor surface. 5 In 2024, four first-in-class drugs have been FDA-approved. The delta-like ligand 3-specific, half-life extended TCE tarlatamab-dlle was approved for recurrent small cell lung cancer (SCLC). 6 It incorporates a novel antigen target in a less immunogenic solid cancer with significant unmet therapeutic needs. The innovative drug platform of adoptively transferred, autologous tumor-infiltrating lymphocytes (TIL) (lifileucel), was approved for advanced melanoma after programmed cell death protein 1 (PD-1)-based or V-Raf murine sarcoma viral oncogene homolog B (BRAF)-inhibitor-based therapy. 7 This personalized treatment is derived from the patient’s own tumor and targets multiple tumor antigens. The interleukin (IL)-15 receptor agonist nogapendekin-alfa inbakicept-pmln (N803) plus bacillus Calmette-Guéri (BCG) was approved for BCG-unresponsive non-muscle-invasive bladder cancer. 8 This molecule has both a unique mechanism of action, and efficacy in a tumor with no good treatment options. Finally, afamitresgene autoleucel is the first approved engineered T-cell receptor (TCR)-T cell therapy, which recognizes the melanoma-associated antigen A4 (MAGE A4) antigen, and is approved for adults with advanced synovial sarcoma previously treated with chemotherapy. 9 This is also the first engineered T-cell therapy approved for a solid tumor.

The rate of clinical progress in IO over the last decade is unprecedented in oncology. Concurrently, the rapid discovery of novel drug targets and the development of new tools for molecular engineering have created a treasure trove of unique molecules currently in advanced preclinical or early clinical studies. These are the agents and drug platforms that will drive the next wave of FDA approvals in cancer IO. However, the field is confronting significant headwinds in the clinical trials and drug delivery ecosystem that will likely hamper our ability to efficiently deliver new IO drugs to patients unless they are addressed. These include excessive regulatory burdens, long delays in trial activation, and the enormous cost of clinical trials that results in a high drug price-point for patients. Compounding these challenges are shortages in both the clinical and research workforce that must be addressed to support continued progress in the field. Although this manuscript is focused on opportunities and challenges in the USA, multiple systemic inefficiencies, some similar and some distinct, also slow drug development in the European Union and beyond.

To galvanize the field and capitalize on the enormous progress we have made, the Society for Immunotherapy of Cancer (SITC) has established a goal of 100 new approvals of unique cancer immunotherapies over the next decade. Supporting this goal, SITC developed a series of manuscripts that identify areas of challenge and opportunity, the first of which provided a broad, high-level overview. 10 This manuscript, which is focused on adapting clinical trials to the unique features of IO drugs, is one of three others that focus on IO mechanisms of antitumor immunity, toxicity, and resistance, novel IO constructs, host and environmental factors that impact immunity, and premalignant immunity. As described in this overview focused on clinical trials, SITC aims to engage diverse stakeholders to deploy innovations in clinical trial design, novel biomarkers for patient selection/stratification and clinical trial endpoints, employ new tools in data science to accelerate clinical development, generate advances in regulatory science, streamline the clinical trials ecosystem, and expand the translational and clinical workforce to accelerate the delivery of novel cancer immunotherapies to patients for cancer treatment, interception, and ultimately prevention.

Clinical trial design and endpoint opportunities

The mechanisms of action of cancer immunotherapies are distinct from conventional oncology agents. Thus, traditional oncology clinical trial methodology often falls short, especially with respect to development strategy and measurement of effect. Cancer drugs have historically been developed by initially looking for activity in heavily treated patients, then advancing the investigations to earlier lines of therapy. Patients with advanced cancer are known to be relatively immunosuppressed due both to cancer burden and prior treatments. They thus may have a greater number of active immune resistance pathways than patients with early-stage malignancies. Additionally, early-phase trials studying a new IO in a late-stage cancer population may not provide a robust assessment of either acute-term or long-term toxicity, particularly for the new agent combined with an approved IO agent. This is because patients participating in such earlier phase trials are typically selected for those who did not experience substantial toxicity to the approved IO agent previously, and thus may not be representative of a more general population. These observations call for innovative trial designs that rapidly evaluate the safety and clinical activity of novel IO agents alone and combined with approved immunotherapies in both early-stage and late-stage diseases at the earliest stages of drug development. Increasing the use of such an integrated approach should accelerate IO drug development in both early and late disease settings by creating opportunities for potential cross-fertilization of knowledge, and by optimizing fiscal, temporal, and patient resources.

There was an initial lack of confidence within the oncology community surrounding the CTLA-4-specific antibody ipilimumab, the first-in-class ICI approved. In early clinical trials, the response rate and progression-free survival (PFS) as assessed by traditional response criteria such as Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization (WHO), were modest; yet, overall survival (OS) improvement was achieved in the pivotal phase 3 trial. 11 Investigators managed unfamiliar patterns of clinical response such as pseudoprogression and minor tumor regression, coded as progressive or stable disease by traditional response criteria, respectively. These atypical responses were counterintuitively often associated with durable clinical benefits from IO. Thus, unique response patterns combined with new, class-specific immune-related side effects initially complicated the development of anti-CTLA-4 treatment. After we learned how to manage the unique features of anti-CTLA-4 therapy, the greater clinical activity and lower toxicity of anti-PD-1/programmed cell death ligand 1 (PD-(L)1) agents mitigated the concerns around response assessment and toxicity during anti-PD-(L)1 development, and protocols began to allow treatment beyond disease progression.

The adoptive transfer of CAR-T cells, TCR-transduced T cells and TIL face additional novel complexities in clinical development relative to historical chemotherapy approaches. CAR-T therapies have had profound impacts on hematologic cancers, yet difficulties in developing clinically and commercially successful products remain. Some of these include prolonged manufacturing times, the tremendous financial capital required to run both early phase and randomized confirmatory studies, and access to study subjects for clinical trials of iterative cell engineering procedures. Cell therapy for solid tumors is also on the verge of having a transformational impact, bringing additional complexity. Screening solid tumor patients who are reasonable candidates for tumor resection and systemic conditioning, have the appropriate human leukocyte antigen (HLA) background for TCR therapy, or express the target tumor antigen for CAR-T cell or TCR-T cell therapy is both resource-intensive and time-intensive. The use of comprehensive next-generation sequencing (NGS) technology will streamline, simplify, and personalize screening for clinical trials and approved IO therapies in the clinic.

Despite these challenges, IO has clearly transformed the oncology landscape. Table 1 outlines common IO trial designs. Initially, trial designs focused on treatment-refractory, but IO-naive patients ( figure 2 ), with substantial success observed across many tumor types. In fact, the treatment of relatively modest numbers of patients led to regulatory approval and evaluation in earlier lines of therapy. Two of the most dramatic examples of this were single-arm phase 2 trials examining the genomic biomarkers of microsatellite instability (MSI) and high tumor mutational burden (TMB), which facilitated the approval of pan-tumor indications. 12 13

Paradoxically, success with single-arm trials in heavily treated patients, which often lacked stringent biomarker stratification, set the stage for a period of malaise in drug development. Anti-PD-(L)1 agents combined with conventional drugs received accelerated approval in settings where a clinical signal was detected, but the long-term benefit was not definitively established as required by the FDA. As a result, several accelerated approvals have subsequently been retracted by trial sponsors. 14 This reality, despite a robust pipeline of innovative, promising IO drugs with diverse mechanisms of action, shaped the perception by some that IO may currently overpromise and underdeliver. This perception has inevitably led to difficulty raising funds to support novel IO drug development in the biotech space, resulting in the failure of multiple biotech companies. As these discovery-oriented biotech companies ultimately feed the large pharma drug pipeline, this dynamic puts the entire IO ecosystem at risk. These diverse factors highlight the complexity of host antitumor immunity, the impact of the lack of effective patient selection for IO trials, and the shortcomings of the ecosystem that develops IO agents that harness the antitumor immune response for therapeutic benefit.

After preliminary safety assessment in advanced disease, many trial sponsors now position investigational drugs in earlier lines of therapy for safety and efficacy assessment in less heavily treated patients. This strategy reflects more classic drug development paradigms in randomized and/or biomarker-informed phase 2 studies in anti-PD-(L)1-treatment-naïve populations. Additionally, opportunity spaces are emerging to investigate novel agents in the neoadjuvant setting. This strategy has yielded new biological insights that support evaluating promising neoadjuvant observations in definitive phase 3 trials. 15 16 Neoadjuvant, perioperative, and adjuvant trial spaces are currently the areas of highest interest for anti-PD-(L)1 agents. It is likely that most patients who receive anti-PD-(L)1 in the future will receive these agents prior to the development of metastatic disease, which may impact the risk/benefit profile of newer IO drugs tested in advanced disease. Moreover, the risk/benefit trade-off is different in patients with early-stage cancers for which non-IO treatment options with curative potential are frequently available. For early-stage disease, it is important to determine how much IO exposure is required to maximize benefits and minimize toxicity. This also highlights the need for intense initial then sustained long-term monitoring and reporting of adverse events given the life-long impact of some immune-related adverse events.

The development of CAR-T cell therapy in hematologic cancers followed the traditional paradigm of initial testing in treatment-refractory disease and then in earlier lines of therapy; whether this approach will be feasible in solid tumors is unknown. Major issues include defining appropriate control arms for randomized studies, and effectively evaluating the contribution of components for cell therapies incorporating lymphodepleting chemotherapy and/or IL-2. Only one study of TIL therapy in solid tumors has been randomized; 17 other studies are ongoing or planned. 18 Given the increasing use of ICI in the neoadjuvant, perioperative, and adjuvant settings, many patients who develop metastatic disease will be ICI-experienced or refractory. Thus, early identification of appropriate candidates for adoptive cellular therapy will be critical, and considerations for patient stratification may be complicated.

Phase 3 or 4 trials can be used to refine dose intensity, length of treatment, toxicity risks, and other considerations unique to specific subpopulations of patients. For example, in the perioperative setting, robust debate about the need for three-arm or four-arm trials prior to approval to identify whether treatment pre-surgery, post-surgery, or both are required for optimal patient benefit is ongoing. 19 Beyond these questions, IO strategies for cancer interception or prevention are receiving increasing interest, with early data supporting IO to interrupt cancer development. 20

It is critical to rigorously evaluate the mechanism of action of any emerging IO in early-phase trials. New agents with monotherapy activity in treatment-refractory patients can be rapidly evaluated in earlier disease settings. Immunotherapies with modest monotherapy activity or activity within a biomarker-selected population are more challenging to evaluate. Here, the patient population, trial design, and primary clinical endpoints must be very carefully chosen. Traditional endpoints such as objective response rate (ORR), PFS, event-free survival (EFS), and OS may poorly describe the potential impact of a new therapy. Instead, detailed pharmacodynamic analysis, rigorous assessment of the extent of tumor shrinkage, determining the disease control rate (DCR) at a fixed point in time, and measuring novel dynamic biomarkers, such as circulating tumor DNA (ctDNA), may help identify an agent with clinical activity. For example, the ORR underestimates the clinical benefit of tebentafusp, and ctDNA monitoring can more effectively guide patient care. Building on these observations, ctDNA monitoring has been used to evaluate continuing treatment with pembrolizumab or treatment intensification in non-SCLC (NSCLC). 21 22 Thus, ctDNA evaluation in adaptive clinical trials can guide continuing open-ended treatment, treatment intensification, or treatment de-escalation. Underlying such an adaptive therapeutic strategy is the observation that long-term disease control represents a hallmark of successful IO. Finally, when multiple immune agents are tested in a regimen, appropriately sequencing them may be important.

There is intense interest in the use of novel surrogate clinical endpoints (such as ctDNA) to accelerate the evaluation of new IO agents. Leveraging the durability of response with IO, treatment-free survival (TFS) has gained substantial support as a patient-centric consideration, particularly with ICI-based therapies. 23 24 In addition, composite endpoints including multiple efficacy endpoints (ORR and PFS) or a mix of efficacy endpoints and safety thresholds may also be informative in early phase studies. Additionally, combining an efficacy endpoint such as OR with ctDNA or a pharmacodynamic measure may be relevant, provided the latter is highly validated. One of the most promising surrogate endpoints in oncology has been the complete pathologic response (pCR) to neoadjuvant therapy, which has predicted favorable long-term outcomes at the patient level. For IO, long-term clinical benefit is also associated with major pathologic response (mPR), defined as a residual tumor of 10% or less. 25 The regulatory landscape surrounding the use of pathologic response as a trial endpoint for regulatory approval remains uncertain, as its surrogacy with longer OS has not yet been demonstrated at the trial level. Finally, drug developers should remain cognizant of the power of machine learning and artificial intelligence (AI) for clinical trial analyses. For example, radiomic analysis may soon enable a patient enrichment strategy to detect clinical signals, 26 thus accelerating drug development programs.

As we evolve our clinical trial designs and endpoints, an urgent need to support more effective drug and biomarker development is the generation of preclinical models that more accurately recapitulate human immunobiology. While millions of people worldwide have received immune checkpoint-blocking antibodies, we still do not know how they work in vivo. The heterogeneity of responses observed underscores our lack of understanding of their mechanisms of action and the host factors that underlie response and resistance in patients with cancer. Importantly, we see similar heterogeneity in the efficacy of these immunotherapies in preclinical models. This holds true of a specific cancer type, and in the context of a defined genetic background. This response heterogeneity in both human and preclinical models likely reflects the intrinsic capacity of the immune system to integrate multiple inputs to generate an adaptive response (or not) in the context of microenvironmental and macroenvironmental signals. This is a critical difference between IO and highly targeted precision medicine therapies. Thus, we need not only more relevant preclinical models, but also more robust data analysis methodologies that better account for the adaptive nature of the immune system.

Dose optimization considerations

The traditional cancer drug development paradigm assumes that the highest tolerable dose is also maximally effective. Although this was reasonable for cytotoxic agents, this association cannot be assumed for immunotherapies. Figure 3 shows several possible relationships between dose and dose-limiting toxicity (DLT) for anti-cancer therapies with different levels of toxicity (all with the same relationship between dose and clinical response). Assumptions for the maximum tolerated dose (MTD) being the optimal dose have been based on the shape and relative location of the dose-toxicity curve (traditional) and dose-efficacy curve (clinical response). There is a therapeutic window for dose that is relatively narrow—only a few doses have activity that is not overly toxic (dose levels 3 and 4 in figure 3 ). For other scenarios described by flat or right-shifted dose-toxicity curves, there are doses lower than the MTD that show high ORRs with relatively low toxicity. Dose optimization strategies for immunotherapies should seek to understand both the dose toxicity and the dose efficacy relationships. In figure 3 , dose level 6 would be optimal for the shifted or flat toxicity curve scenarios: it has high efficacy at dose level 6 with almost no gain in efficacy at higher doses and the toxicity is below an acceptable threshold for the DLT rate.

While understanding the relationship between dose and efficacy and between dose and toxicity is critical to drug development, it may be determined that a broad range of doses have similar efficacy and/or toxicity and, thus, there is not a single dose that could be deemed “optimal” for IO therapies. Using PD-1 ICIs as an example, neither pembrolizumab 27 nor nivolumab 28 reached an MTD in phase 1 studies, and both drugs were active at doses much lower than the highest doses administered and with a relatively flat dose-response curve.

One strategy for dose optimization promoted by the FDA Project Optimus incorporates both efficacy and toxicity. A somewhat traditional phase 1 study design might be used to explore toxicity rates for a range of dose levels using dose escalation with relatively few patients per dose level. Based on observed toxicities (both low and high grades in early cycles), pharmacokinetics, and pharmacodynamics at various dose levels, two or more doses would be selected for further evaluation in a dose-ranging study. The dose-ranging study may have a different patient population than the phase 1 study and would have primary endpoints of efficacy and tolerability (including long-term safety and tolerability endpoints) to help select an optimal dose. Another approach of considerable interest to patient advocates is to provide a range of potential doses that can be individually titrated for each patient.

Along these lines, the FDA Oncology Center for Excellence (OCE) has initiated various projects relevant to the development of cancer immunotherapies. 29 They span different aspects of drug development and approval to promote optimization, expediency, and to ensure approved agents provide more than incremental clinical benefit. Those of most relevance are provided in table 2 , with more information available on the OCE website.

The role of patient advocates in clinical trials

Involving patient advocates in the planning, conduct, and dissemination of clinical trial results helps to ensure that trials answer questions important to patients, that the burden of trial participation is minimized, and that communication about the trial occurs in a patient-friendly way ( box 1 ), thus facilitating rapid accrual and excellent compliance. Advocate input is especially essential in two areas that directly impact participants: patient-reported outcomes (PROs), and trial-related communication. PROs directly assess participants’ perceptions of adverse events and their Health-Related Quality of Life (HR-QoL). The collection of PROs is becoming standard practice in oncology clinical trials. The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) 30 is a commonly used instrument that assesses patients’ experience of toxicities in oncology trials. However, it is not focused specifically on toxicities associated with immunotherapies, where late-occurring toxicities are more likely. The distinct pattern and timing of immune-related adverse events warrant the development of PRO instruments specifically tailored to immunotherapies. 31 32 In addition to PROs, advocates can provide critical input to guide the development of non-technical, visually attractive, balanced, patient-facing trial materials, and help shape informed consent discussions. Advocates can also assist in crafting plain-language summaries of trial results for patients and the public.

Strategies for maximizing benefit and minimizing burden on trial participants

Maximize benefit

Power trials to achieve large benefits

Allow patients to cross over

Include patient-reported outcomes and Quality of Life measures

Minimize the number of patients who receive a placebo or standard of care

Ensure the trial will be completed rapidly to remain meaningful to future patients

Broaden eligibility requirements

Provide personalized treatments

Return results (aggregate and individual)

Allow patients to donate their tissue/data for future research

Minimize burden

Schedule an appointment for patient convenience

Improve access by opening sites convenient for diverse patient groups

Prioritize the most important research procedures

Be mindful of direct and indirect financial burdens of trial participation, and provide appropriate compensation

Be proactive about providing supportive care for toxicities

Biomarker opportunities

With thousands of cancer IO drugs under investigation, biomarker development is critical to identify the right therapy for the right patient at the right time. Incorporating biomarkers into drug development at the earliest stages should accelerate clinical research and optimize routine clinical practice after drug approval. Biomarkers are biologic data associated with the likelihood that a patient will respond to a given treatment (predictive biomarkers) or that convey a better or worse prognosis with currently available therapies (prognostic biomarkers). Some biomarkers are both predictive and prognostic (for example, peripheral soluble PD-L1 across cancers, and somatic STK11 mutations co-occurring with KRAS mutations in lung cancer). 33 34 Biomarker development has historically relied on the collection of tumor tissue and blood samples. Profiling to define static biomarkers at baseline as well as dynamic changes on treatment can lend deep insights into the mechanism of action and efficacy of a drug. Examples of dynamic biomarkers are ctDNA kinetics and cytokine signatures in the blood, which may better capture systemic tumor burden and quality of the antitumor immune response, respectively. 35 36 While biomarkers are often developed for patient selection, there is increasing interest in on-treatment biomarkers as early indicators of response, biomarkers of toxicity, and biomarkers associated with the pharmacodynamic activity of the drug.

There are only a few validated biomarkers to guide IO decisions ( figure 4 ). PD-L1 is a biomarker approved by the FDA to guide therapeutic decisions in certain tumor types such as triple-negative breast cancer (TNBC) 37 and NSCLC. 38 In metastatic TNBC, PD-L1 expression guides the selection of patients for treatment with PD-1 blockade and chemotherapy, and in NSCLC it dictates whether chemotherapy should be included with PD-1 blockade, or if combination immunotherapies should be pursued. It is not employed in some other tumor types where it is not predictive, such as melanoma 39 or hepatocellular carcinoma. 40 TMB, routinely computed by many commercial NGS panels, is also an FDA-approved biomarker. Although the optimal cut-off for TMB remains debated, patients with high TMB may benefit from IO regardless of tumor histology. 13 Importantly, these predictive biomarkers do not always predict a clinical response, as there is a sizeable fraction of cancers with either PD-L1 expression or a high TMB that do not regress with IO. Cancers with MSI by NGS or mismatch repair deficiency (dMMR) by immunohistochemistry are hypermutated and typically harbor an exceptionally high TMB that drives deep and durable responses to IO; 12 41 42 however, even MSI-high is an imperfect predictive biomarker.

As TMB represents only a crude measure of tumor foreignness, emerging approaches that capture mutations, co-mutations and mutational signatures uniquely associated with ICI response hold promise. 43 45 Similarly, novel transcriptomic signatures based on bulk RNA sequencing may identify tumors with an inflamed tumor microenvironment (TME) that can drive tumor elimination in the context of ICI. 46 At a deeper level, machine learning methodologies are now enabling bulk and single-cell resolution assessment of the transcriptomic, epigenetic, and metabolic state of tumor cells, stromal cells and infiltrating immune cells, and cells in the neighboring parenchyma and draining lymph nodes and lymphatics ( figure 4 ). 47 Additionally, spatial proteomic and transcriptomic platforms can provide a snapshot of the TME architecture. Spatial determinants of response to IO might include the excluded or inflamed immunophenotype, or the presence and maturation status of tumor-associated tertiary lymphoid structures (TLS). TLS has been shown to correlate with response to checkpoint blockade. 46 48

Bridging the biology of antitumor immune responses with innovative technologies that provide real-time, minimally invasive monitoring of systemic tumor burden, liquid biopsies provide a window into both tumor clonal evolution and the systemic immune milieu across diverse metastatic sites. 36 Molecular response based on ctDNA detection during ICI consistently predicts clinical outcomes and is now often tested in interventional clinical trials. 22 A growing body of ctDNA studies supports the potential clinical utility of ctDNA molecular response as an early endpoint of ICI response. Thus, liquid biopsy-tailored approaches may facilitate drug development by providing a rapid read-out of therapeutic efficacy. Moreover, ctDNA-informed treatment escalation or de-escalation can be evaluated in clinical trials. As IO enters the therapeutic arena of early-stage cancers, minimal residual disease (MRD) detected by ctDNA may serve as a real-time monitor for disease burden during neoadjuvant or perioperative IO, and predict long-term outcomes. 49 50 As the analytical and clinical sensitivity of MRD assays continues to improve, ctDNA MRD may enable the navigation of an expanding clinical trial landscape for patients with early-stage cancers. 51 Blood-based profiling can also enhance our understanding of the systemic immune milieu. The neutrophil-to-lymphocyte ratio (NLR) is both prognostic and predictive, 52 and an even deeper analysis of systemic lymphoid and myeloid populations reveals further biologic granularity. In tandem, profiling peripheral cytokines and chemokines can identify both biomarkers and therapeutic targets. Many studies have evaluated inflammasome cytokines, such as IL-1. Measuring and potentially manipulating Type 1 (Th1) or Type 2 (Th2) cytokines, known to promote or stymie antitumor immunity respectively, is also under intensive investigation. 53 It is likely that composite biomarkers that incorporate aspects of both tumor and host immunobiology will be most informative ( figure 4 ).

While the technologies to query the TME and systemic immune milieu in patients at baseline and on therapy have rapidly progressed, these new approaches have highlighted several challenges that currently limit the implementation of tissue-based and blood-based biomarkers into clinical trials. One key limitation is the lack of standardization. First, even among trials within a single sponsor or cooperative group, each trial may collect different biospecimens at different time points, and potentially process and preserve samples in disparate manners. Second, blood and tissue analyses are often performed using distinct platforms. The use of specific platforms and modes of analysis is heterogeneous due to significant expense, thus limiting cross-trial comparisons. Third, when relatively limited assessments are selected for logistical or financial reasons (predefined cytokine or flow cytometry panels for example), generalizability is often limited due to heterogeneity between patients, and among disease sites within a given patient. This highlights the importance of sampling multiple sites of disease when evaluating biomarkers, as biomarker expression between two biopsies within the same patient may diverge. Biologic differences based on stage add further complexity. It is unclear the extent to which resected tumors from patients with early-stage disease may represent the TME of widely metastatic disease. Furthermore, the immunobiology of premalignant tissue is likely to be even more distinct. While neoadjuvant and window-of-opportunity trials are invaluable given the sheer volume of tumors available for biomarker testing, biomarker findings in the perioperative setting must always be validated across the disease spectrum, where the local and systemic immune milieus may differ. The neoadjuvant setting further represents a unique opportunity to relate tumor-based biomarkers to liquid biopsy-based biomarkers in a time-efficient manner.

Ideally, biological samples for biomarker development are assessed at baseline, on treatment, and at disease progression. As this requires multiple tissue biopsies and/or blood samples from a given patient, the ethics of this have been widely discussed by researchers, ethicists, and patient advocates. 54 55 The value of the information gained versus the risk to participants must be weighed. While patients are often willing to donate biologic samples, sites are often reluctant to request them due to logistical burdens on both the patient and the study team, the extra resources required, and a lack of understanding of the potential value of the information gained. Blood-based biomarkers and non-invasive biomarkers such as radiomics and molecular imaging may be less cumbersome and risky than tissue biopsies, and thus likely to be more readily implemented.

Biomarker assays must be validated across patient samples and clinical settings, ideally in biospecimens with standardized, straightforward collection procedures. The biologic signal of interest should be highly stable, so that tissue formalin fixation time, or time from blood collection to centrifugation and/or cryopreservation, will not significantly alter a protein or genomic signal. The biomarker assay must be performed consistently across locations and operators, and ideally not require highly specialized training. Finally, while significant investment is required for assay development and standardization, the ultimate biomarker for clinical use should incur minimal expense to facilitate future global implementation to guide routine clinical use of the drug.

Clinical trial operations and ecosystem opportunities

The complexity of biobanking processes, procedures, and ethics during the conduct of clinical trials reflects the clinical trials operations landscape beyond IO and cancer, which is fraught with inefficiencies and challenges. The focus of the manuscript is US-centric, but it is critical to recognize that inefficiencies in systems supporting clinical trials also affect the clinical trial enterprise outside the USA. Some of these inefficiencies are shared with the USA, but others are unique, and often related to differences in regulatory oversight between countries. Difficulties in protocol development, regulatory approvals, site selection, patient enrollment, retention, and data collection/analysis are so significant that only approximately 12% of clinical trials are ultimately successful. 56 The intricacies of trial execution and design preclude many community sites from participating in clinical trials, thereby limiting both patient access and the diversity of patients enrolled in potentially life-saving cancer therapies. Ultimately, this slows the approval of new therapies. Indeed, cancer clinical trial offices at North American cancer centers have a median annual operating budget of US$8.2 million and more than 100 employees to accommodate the required financial, regulatory, clinical and data operations requirements. 57 While many patients with cancer express interest in participating in clinical trials, especially those with poor prognosis and limited treatment options, other patients do not trust the medical establishment that sponsors clinical trials and fear they will be treated as “guinea pigs”. Patients who are interested in trial participation often have difficulty identifying trials for which they are eligible, or encounter financial, travel, time, or other impediments that discourage them.

One proposed strategy to improve trial operational efficiency is the centralization of clinical research resources required for site selection and study start-up. Currently, trial sponsors and contract research organizations routinely request redundant and/or non-essential information, causing delays, increased burdens on research staff, and increased costs. Recommendations from a 2020 American Society of Clinical Oncology (ASCO) Task Force, formed to assess burdens and challenges with feasibility assessments (FAs), include: (1) implementing a streamlined and uniform FA process across trials and sponsors; (2) minimizing and standardizing questions; and (3) leveraging technology to centralize FAs, facilitate communications, and reduce redundancies. 58 Implementing these strategies will allow greater focus on factors identified as crucial site-related qualities, including the ability to reach enrollment goals and meet necessary data quality standards. 59

Achieving enrollment goals is also contingent on reasonable and applicable eligibility criteria. In the current competitive cancer therapy approval landscape, eligibility criteria have become increasingly restrictive, creating unnecessary barriers to patient access. 60 62 A recent systematic evaluation of the effect of different eligibility criteria on cancer trial populations and outcomes with real-world data using an AI computational framework suggests that many patients who were not eligible under the established trial criteria actually could potentially benefit from the investigational treatments. 63 Additionally, trials with more relaxed eligibility thresholds (eg, bilirubin, platelets, hemoglobin and alkaline phosphatase) did not have increased treatment withdrawals due to adverse events compared with trials with more stringent eligibility thresholds across different types of cancer. 63 Similarly, a 2022 LUNGevity Foundation working group, convened to streamline lung cancer clinical trials, identified 13 common eligibility categories with key factors to consider during development to prevent unnecessary limitations. 60

Maximizing the efficiency of clinical research operations is also key to implementing clinical trials, accruing participants, obtaining quality data, and delivering new IO drugs to patients. The National Cancer Institute (NCI) Clinical Trials and Translational Research Advisory Committee (CTAC) put together a Strategic Planning Working Group in 2019 to work toward a vision of “flexible, faster, simpler, less expensive, high-impact trials that seamlessly integrate with clinical practice”. 64 Recommendations from their Streamlining Clinical Trials Working Group provide a framework to build on and include streamlining data collection, use of standard practice data principles and data elements, and optimizing the use of electronic health records (EHR) to support clinical trials through efforts such as data extraction and EHR study builds. 65 These recommendations directly impact clinical trial sites and their participation in studies. Ensuring that sites have a voice in the development of these key strategies is critical at both the national as well as the local level. The inclusion of site research leaders and study coordinators at every level of protocol design and implementation will also help facilitate better operational clarity and feasibility. This practical, real-world line-of-sight could reduce logistical barriers, provide feedback to improve study processes such as slot and cohort management, and identify potential budget, contractual, billing, and compliance issues that could lead to delays and future protocol amendments. Participating in networks and consortia such as the National Cancer Institute Clinical Trials Network (NCTN) is one way to maximize access to trials and the efficiency of clinical research operations while potentially reducing administrative and regulatory redundancies. This allows research staff more time to focus on meeting enrollment goals and working with investigators to ensure good clinical practice and care.

Increasing diversity in clinical trials is a pressing priority in cancer research. Recognizing that people enrolled in oncology clinical trials tend to be younger, healthier, and less racially, ethnically, and geographically diverse than people seen in clinics, the FDA issued a draft guidance for diversity plans to improve enrollment of trial participants from underrepresented racial and ethnic populations. 66 67 As about 20% of drugs have different effects based on a patient’s race, concerted efforts are urgently needed to recruit diverse patient populations to investigational studies to ensure that approved cancer therapies are safe for all. 68 Ochsner Health, comprised of 46 hospitals and 370 clinics and urgent care centers in Louisiana, prioritized minority enrollment in clinical trials as an institutional goal in 2023. To achieve this goal, they conducted a multimedia campaign to educate patients, created a Center of Health Equity with Xavier University, engaged the community, formed a patient council, implemented housing and transportation programs to reduce barriers to clinical trial enrollment, and created a pipeline of research staff from the community. Through these efforts, which have been similarly validated in other settings, Ochsner achieved 36% minority enrollment in clinical trials for 2023. 69 Additional considerations for achieving diversity in clinical trials include LGBTQ+, elderly, and disabled patients. Emerging guidance 70 and support for the implementation of Decentralized Clinical Trial activities will also provide research sites with greater ability to provide some trial-related activities at locations beyond traditional clinical trial sites, thus broadening access for patients and community partners.

Workforce shortages have affected goals for efficient and representative clinical trial enrollment, with 63% of US-based clinical research sites identifying staffing and retention as the top research challenge. 71 Due to a lack of career development opportunities, key members of the clinical trial team, such as data managers, study coordinators and research nurses, work in these settings for short periods of time before moving on to a better-defined career path. 72 Opportunities to reduce dissatisfiers include improved clarity in protocols and data submission requirements, reduced collection of unnecessary data, streamlined regulatory and rostering processes, increased consistency and standardization between sponsors and research bases, improved clinical trial accessibility for underserved populations, centrally provided protocol-specific EHR treatment plans, and centralized training for research staff and investigators. These recommendations were developed by a cross-network Research Operations Working Group, comprised of representatives from NCI Oncology Research Program (NCORP)/NCTN Research Bases (Southwest Oncology Group (SWOG), Alliance, NRG [ NRG Oncology is a NCTN group created through the coordinated efforts of the National Surgical Adjuvant Breast and Bowel Project ( N SABP), the Radiation Therapy Oncology Group ( R TOG), and the Gynecologic Oncology Group ( G OG)] and Eastern Cooperative Oncology Group-American College of Radiology Imaging Network [ECOG-ACRIN]), then shared with NCTN, NCORP and CTAC leaders, and are currently being implemented. Pilot projects are also underway with several NCTN groups related to direct electronic medical record to electronic data capture data collection.

Advanced practitioners (APs) (including nurse practitioners and physician assistants) represent a growing and critical component of the oncology workforce with more than 80% of US oncology practices employing APs, many of whom function in research roles. 73 Recent revisions in NCI’s Cancer Therapy Evaluation Program (CTEP) policies allow APs to register as enrolling investigators and sign treatment orders for investigational agents without a physician co-signature. 73 Future research frameworks should consistently include AP researchers in critical research activities including feasibility reviews, assessment of enrollment goals, site initiation visits and investigator meetings. Successful diversification of the clinical trial workforce must include a broad array of professions. Opportunities to foster professional advancement for all members of the research team should be identified and implemented.

Conclusion

Cancer IO has clearly demonstrated its power over the last decade as the first wave of immune-based drugs transformed the patient experience. The field is now clearly at an inflection point. Discovery and translational researchers effectively leveraged the science of IO to create a robust and heterogeneous pipeline of highly innovative, first-in-class immunotherapies with significant therapeutic promise. These unique agents clearly require further innovations in clinical, manufacturing, and regulatory science for their effective delivery to patients and providers. A major barrier in bringing these new IO drugs to patients is the clutter and redundancy built into the current clinical trials ecosystem. SITC highlighted this challenge in its program on the Crisis in Clinical Research, advocating for key reforms that will streamline clinical trial operations across the stakeholders in the drug development ecosystem. From a research perspective, deploying efficiencies in clinical trial design and incorporating the use of surrogate clinical endpoints that reflect long-term clinical benefit at early time points will accelerate clinical progress. Appropriate patient stratification based on clinical variables, histopathological features, or discrete biomarker expression in clinical trials will further hasten drug development. The analysis of baseline, on-treatment, and post-progression clinical trial biospecimens will lend important insights into mechanisms of IO response, resistance, and toxicity, enabling biomarker-driven patient selection and management. Safely moving investigational therapies from advanced disease into the neoadjuvant or adjuvant settings should also accelerate progress since the therapeutic impact in the early disease setting is likely much greater. The landscape of promising immune-based strategies for the interception of developing malignancy and upfront immunoprevention in high-risk individuals is also growing.

SITC has prioritized multiple programs designed to capitalize on these opportunities by maintaining open dialog and integrating the thinking of key drug development stakeholders. The SITC Drug Development Symposium in fall 2024 is newly updated. It is designed to deliver foundational information, and facilitate vibrant and open discussion among key around the most impactful opportunities and pressing challenges in IO drug development today. Programming at SITC’s 2024 Annual Meeting included a symposium on TIL therapy, and a workshop on immunoengineering. The SITC Spring Scientific in 2025 will focus on cell therapy for solid tumors. Society initiatives designed to inform patient stratification and selection are focused on primary and secondary IO drug resistance, and the critical role of informative biomarkers in accelerating IO drug development. The Society has convened roundtables with biotech, pharma, and the FDA to discuss surrogate clinical endpoints as a near-term measure of long-term clinical benefit to hasten drug approval timelines, and release criteria for complex biologics such as cell-based therapies. SITC has a major focus and investment in developing the next generation of discovery, translational, and clinical investigators, and offers numerous programs to support them. We offer numerous travel awards to the annual meeting, and the prestigious Presidential award goes to the highest-ranked abstract by an early career investigator. We have also implemented a 1 day program at the annual meeting designed to introduce biomedical research and practice to undergraduates from underrepresented groups in the community where the annual meeting is held. We also support the careers of new investigators through research fellowship awards, the annual SITC Winter School focused on fundamental IO and the concurrent SITC Clinical Immuno-Oncology Network (SCION) program focused on developing high-quality clinical protocols. SITC collaborates with the Association of Cancer Care Centers (ACCC)to reach community clinicians, and offers clinician training through its Advances in Cancer Immunotherapy (ACI) program. SITC will continue to use its “big tent” approach to foster dialog that engages and integrates diverse members of the drug development community, including academia, biotech, pharma, the financial community, the FDA, the NCI, community oncologists, and patients themselves, with the goal of synergistically working together to rapidly bring the latest innovative cancer immunotherapies to the patients waiting for them.

Acknowledgements

The authors wish to thank the Society for Immunotherapy of Cancer (SITC) staff including Mary Dean for strategic guidance, Christina Mooney for project management and Kaitlin Johnson, PhD for editorial assistance. Additionally, the authors thank SITC for supporting the manuscript development.

Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Patient consent for publication: Not applicable.

Ethics approval: Not applicable.

Provenance and peer review: Not commissioned; externally peer reviewed.

References

1 Tawbi HA Sullivan RJ Feltquate D et al Society for Immunotherapy of Cancer (SITC) checkpoint inhibitor resistance definitions: efforts to harmonize terminology and accelerate immuno-oncology drug development J Immunother Cancer 2023 11 e007309 10.1136/jitc-2023-007309 37487665 PMC10373737

2 Berdeja JG Madduri D Usmani SZ et al Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study The Lancet 2021 398 314 24 10.1016/S0140-6736(21)00933-8 34175021

3 Rodriguez-Otero P Ailawadhi S Arnulf B et al Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma N Engl J Med 2023 388 1002 14 10.1056/NEJMoa2213614 36762851

4 Chari A Minnema MC Berdeja JG et al Talquetamab, a T-Cell–Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma N Engl J Med 2022 387 2232 44 10.1056/NEJMoa2204591 36507686

5 Nathan P Hassel JC Rutkowski P et al Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma N Engl J Med 2021 385 1196 206 10.1056/NEJMoa2103485 34551229

6 Ahn M-J Cho BC Felip E et al Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer N Engl J Med 2023 389 2063 75 10.1056/NEJMoa2307980 37861218

7 Chesney J Lewis KD Kluger H et al Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study J Immunother Cancer 2022 10 e005755 10.1136/jitc-2022-005755 36600653 PMC9748991

8 Chamie K Chang SS Kramolowsky E et al IL-15 Superagonist NAI in BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer NEJM Evid 2023 2 EVIDoa2200167 10.1056/EVIDoa2200167 38320011

9 D’Angelo SP Araujo DM Abdul Razak AR et al Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial The Lancet 2024 403 1460 71 10.1016/S0140-6736(24)00319-2 PMC11419333 38554725

10 Emens LA Romero PJ Anderson AC et al Challenges and opportunities in cancer immunotherapy: a Society for Immunotherapy of Cancer (SITC) strategic vision J Immunother Cancer 2024 12 e009063 10.1136/jitc-2024-009063 38901879 PMC11191773

11 Hoos A Ibrahim R Korman A et al Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy Semin Oncol 2010 37 533 46 10.1053/j.seminoncol.2010.09.015 21074069

12 Le DT Uram JN Wang H et al PD-1 Blockade in Tumors with Mismatch-Repair Deficiency N Engl J Med 2015 372 2509 20 10.1056/NEJMoa1500596 26028255 PMC4481136

13 Marabelle A Fakih M Lopez J et al Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study Lancet Oncol 2020 21 1353 65 10.1016/S1470-2045(20)30445-9 32919526

14 US Food and Drug Administration Withdrawn—cancer accelerated approvals 2024 Available https://www.fda.gov/drugs/resources-information-approved-drugs/withdrawn-cancer-accelerated-approvals

15 Long GV Eggermont AM Gershenwald JE et al KEYVIBE-010: Adjuvant coformulated vibostolimab with pembrolizumab versus adjuvant pembrolizumab in patients with high-risk stage II-IV melanoma JCO 2023 41 10.1200/JCO.2023.41.16_suppl.TPS9611

16 Long GV Robert C Hill AG et al 1082O KEYMAKER-U02 substudy 02C: Neoadjuvant pembrolizumab (pembro) and investigational agents followed by adjuvant pembro for stage IIIB-D melanoma Ann Oncol 2024 35 S712 3 10.1016/j.annonc.2024.08.1150

17 Rohaan MW Borch TH van den Berg JH et al Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma N Engl J Med 2022 387 2113 25 10.1056/NEJMoa2210233 36477031

18 Olson D Hong Y Thomas SS et al A phase 3 study (TILVANCE-301) to assess the efficacy and safety of lifileucel, an autologous tumor-infiltrating lymphocyte cell therapy, in combination with pembrolizumab compared with pembrolizumab alone in patients with untreated unresectable or metastatic melanoma JCO 2023 41 10.1200/JCO.2023.41.16_suppl.TPS9607

19 US Food and Drug Administration, American Association for Cancer Research FDA-aacr workshop: how much is enough? trial designs for treatment regimens with multiple phases 2024 Available https://www.aacr.org/professionals/policy-and-advocacy/regulatory-science-and-policy/events/fda-aacr-workshop-how-much-is-enough-trial-designs-for-treatment-regimens-with-multiple-phases

20 Stanton SE Castle PE Finn OJ et al Advances and challenges in cancer immunoprevention and immune interception J Immunother Cancer 2024 12 e007815 10.1136/jitc-2023-007815 38519057 PMC10961508

21 Hassel JC Piperno-Neumann S Rutkowski P et al Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma N Engl J Med 2023 389 2256 66 10.1056/NEJMoa2304753 37870955 PMC11188986

22 Anagnostou V Ho C Nicholas G et al ctDNA response after pembrolizumab in non-small cell lung cancer: phase 2 adaptive trial results Nat Med 2023 29 2559 69 10.1038/s41591-023-02598-9 37814061 PMC10579094

23 Regan MM Werner L Rao S et al Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition-A Pooled Analysis of Patients With Advanced Melanoma J Clin Oncol 2019 37 3350 8 10.1200/JCO.19.00345 31498030 PMC6901280

24 Regan MM Jegede OA Mantia CM et al Treatment-free Survival after Immune Checkpoint Inhibitor Therapy versus Targeted Therapy for Advanced Renal Cell Carcinoma: 42-Month Results of the CheckMate 214 Trial Clin Cancer Res 2021 27 6687 95 10.1158/1078-0432.CCR-21-2283 34759043 PMC9357269

25 Deutsch JS Cimino-Mathews A Thompson E et al Association between pathologic response and survival after neoadjuvant therapy in lung cancer Nat Med 2024 30 218 28 10.1038/s41591-023-02660-6 37903504 PMC10803255

26 Sun R Sundahl N Hecht M et al Radiomics to predict outcomes and abscopal response of patients with cancer treated with immunotherapy combined with radiotherapy using a validated signature of CD8 cells J Immunother Cancer 2020 8 e001429 10.1136/jitc-2020-001429 33188037 PMC7668366

27 Kang SP Gergich K Lubiniecki GM et al Pembrolizumab KEYNOTE-001: an adaptive study leading to accelerated approval for two indications and a companion diagnostic Ann Oncol 2017 28 1388 98 10.1093/annonc/mdx076 30052728 PMC5452070

28 Agrawal S Feng Y Roy A et al Nivolumab dose selection: challenges, opportunities, and lessons learned for cancer immunotherapy J Immunother Cancer 2016 4 10.1186/s40425-016-0177-2 PMC5109842 27879974

29 US Food and Drug Administration OCE programs and projects overview 2024 Available https://www.fda.gov/about-fda/oncology-center-excellence/oce-programs-and-projects-overview

30 National Cancer Institute Patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) Available https://healthcaredelivery.cancer.gov/pro-ctcae 10.1186/s41687-017-0012-7 PMC5934908 29757296

31 Colomer-Lahiguera S Bryant-Lukosius D Rietkoetter S et al Patient-reported outcome instruments used in immune-checkpoint inhibitor clinical trials in oncology: a systematic review J Patient Rep Outcomes 2020 4 58 10.1186/s41687-020-00210-z 32676785 PMC7364679

32 Da Silva Lopes AM Colomer-Lahiguera S Mederos Alfonso N et al Patient-reported outcomes for monitoring symptomatic toxicities in cancer patients treated with immune-checkpoint inhibitors: A Delphi study Eur J Cancer 2021 157 225 37 10.1016/j.ejca.2021.08.026 34536946

33 Oh SY Kim S Keam B et al Soluble PD-L1 is a predictive and prognostic biomarker in advanced cancer patients who receive immune checkpoint blockade treatment Sci Rep 2021 11 19712 10.1038/s41598-021-99311-y 34611279 PMC8492653

34 Manolakos P Ward LD A Critical Review of the Prognostic and Predictive Implications of KRAS and STK11 Mutations and Co-Mutations in Metastatic Non-Small Lung Cancer J Pers Med 2023 13 1010 10.3390/jpm13061010 37373999 PMC10304809

35 Stewart MD Anagnostou V Liquid biopsies coming of age: biology, emerging technologies, and clinical translation- An introduction to the JITC expert opinion special review series on liquid biopsies J Immunother Cancer 2023 11 e006367 10.1136/jitc-2022-006367 36657817 PMC9853210

36 Sivapalan L Murray JC Canzoniero JV et al Liquid biopsy approaches to capture tumor evolution and clinical outcomes during cancer immunotherapy J Immunother Cancer 2023 11 e005924 10.1136/jitc-2022-005924 36657818 PMC9853269

37 Cortes J Rugo HS Cescon DW et al Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer N Engl J Med 2022 387 217 26 10.1056/NEJMoa2202809 35857659

38 Mok TSK Wu YL Kudaba I et al Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial The Lancet 2019 393 1819 30 10.1016/S0140-6736(18)32409-7 30955977

39 Larkin J Minor D D’Angelo S et al Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator’s Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial JCO 2018 36 383 90 10.1200/JCO.2016.71.8023 PMC6804912 28671856

40 Ji JH Ha SY Lee D et al Predictive Biomarkers for Immune-Checkpoint Inhibitor Treatment Response in Patients with Hepatocellular Carcinoma Int J Mol Sci 2023 24 7640 10.3390/ijms24087640 37108802 PMC10144688

41 Le DT Durham JN Smith KN et al Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade Science 2017 357 409 13 10.1126/science.aan6733 28596308 PMC5576142

42 André T Shiu KK Kim TW et al Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer N Engl J Med 2020 383 2207 18 10.1056/NEJMoa2017699 33264544

43 Skoulidis F Goldberg ME Greenawalt DM et al STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma Cancer Discov 2018 8 822 35 10.1200/JCO.2017.35.15_suppl.9016 29773717 PMC6030433

44 Spranger S Bao R Gajewski TF Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity Nature New Biol 2015 523 231 5 10.1038/nature14404 25970248

45 Niknafs N Balan A Cherry C et al Persistent mutation burden drives sustained anti-tumor immune responses Nat Med 2023 29 440 9 10.1038/s41591-022-02163-w 36702947 PMC9941047

46 Cristescu R Mogg R Ayers M et al Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy Science 2018 362 10.1126/science.aar3593 PMC6718162 30309915

47 Zaitsev A Chelushkin M Dyikanov D et al Precise reconstruction of the TME using bulk RNA-seq and a machine learning algorithm trained on artificial transcriptomes Cancer Cell 2022 40 879 94 10.1016/j.ccell.2022.07.006 35944503

48 Helmink BA Reddy SM Gao J et al B cells and tertiary lymphoid structures promote immunotherapy response Nature New Biol 2020 577 549 55 10.1038/s41586-019-1922-8 PMC8762581 31942075

49 Forde PM Spicer J Lu S et al Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer N Engl J Med 2022 386 1973 85 10.1056/NEJMoa2202170 35403841 PMC9844511

50 Provencio M Serna-Blasco R Nadal E et al Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial) J Clin Oncol 2022 40 2924 33 10.1200/JCO.21.02660 35576508 PMC9426809

51 Vellanki PJ Ghosh S Pathak A et al Regulatory implications of ctDNA in immuno-oncology for solid tumors J Immunother Cancer 2023 11 e005344 10.1136/jitc-2022-005344 36796877 PMC9936292

52 Li Y Meng Y Sun H et al The Prognostic Significance of Baseline Neutrophil-to-Lymphocyte Ratio in Melanoma Patients Receiving Immunotherapy J Immunother 2022 45 43 50 10.1097/CJI.0000000000000392 34510106 PMC8654256

53 LaMarche NM Hegde S Park MD et al An IL-4 signalling axis in bone marrow drives pro-tumorigenic myelopoiesis Nature New Biol 2024 625 166 74 10.1038/s41586-023-06797-9 PMC11189607 38057662

54 Overman MJ Ellis LM Joffe S Ethics and the Underreporting of Research Biopsy Findings in Clinical Trials JAMA Oncol 2018 4 1041 2 10.1001/jamaoncol.2018.1002 29799989

55 Levit LA Peppercorn JM Tam AL et al Ethical framework for including research biopsies in oncology clinical trials ASCO 2019 37 2368 77 10.1200/JCO.19.01479 31343905

56 Wong CH Siah KW Lo AW Estimation of clinical trial success rates and related parameters Biostatistics 2019 20 273 86 10.1093/biostatistics/kxx069 29394327 PMC6409418

57 Lee C Werner TL Deal AM et al Clinical Trial Metrics: The Complexity of Conducting Clinical Trials in North American Cancer Centers JCO Oncol Pract 2021 17 e77 93 10.1200/OP.20.00501 33186085 PMC8202063

58 Kurbegov D Hurley P Waterhouse DM et al Recommendations to Streamline and Standardize Clinical Trial Site Feasibility Assessments: An ASCO Research Statement JCO Oncol Pract 2021 17 41 51 10.1200/OP.20.00821 33405975

59 Dombernowsky T Haedersdal M Lassen U et al Criteria for site selection in industry-sponsored clinical trials: a survey among decision-makers in biopharmaceutical companies and clinical research organizations Trials 2019 20 1 12 10.1186/s13063-019-3790-9 31829234 PMC6907246

60 Gerber DE Singh H Larkins E et al A New Approach to Simplifying and Harmonizing Cancer Clinical Trials-Standardizing Eligibility Criteria JAMA Oncol 2022 8 1333 9 10.1001/jamaoncol.2022.1664 35925576 PMC9934063

61 Kim ES Bruinooge SS Roberts S et al Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement J Clin Oncol 2017 35 3737 44 10.1200/JCO.2017.73.7916 28968170 PMC5692724

62 Kim ES Uldrick TS Schenkel C et al Continuing to Broaden Eligibility Criteria to Make Clinical Trials More Representative and Inclusive: ASCO-Friends of Cancer Research Joint Research Statement Clin Cancer Res 2021 27 2394 9 10.1158/1078-0432.CCR-20-3852 33563632 PMC12486295

63 Liu R Rizzo S Whipple S et al Evaluating eligibility criteria of oncology trials using real-world data and AI Nature New Biol 2021 592 629 33 10.1038/s41586-021-03430-5 PMC9007176 33828294

64 National Cancer Institute Streamlining clinical trials working group report 2024 Available https://deainfo.nci.nih.gov/advisory/ctac/0324/Mandrekar2.pdf

65 National Cancer Institute NCTN streamlined data standard practices for ind-exempt trials 2022 Available https://ctep.cancer.gov/protocolDevelopment/templates_applications.htm

66 Oyer RA Hurley P Boehmer L et al Increasing Racial and Ethnic Diversity in Cancer Clinical Trials: An American Society of Clinical Oncology and Association of Community Cancer Centers Joint Research Statement J Clin Oncol 2022 40 2163 71 10.1200/JCO.22.00754 35588469

67 US Food and Drug Administration Diversity action plans to improve enrollment of participants from underrepresented populations in clinical studies n.d. Available https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diversity-action-plans-improve-enrollment-participants-underrepresented-populations-clinical-studies

68 Ramamoorthy A Pacanowski MA Bull J et al Racial/ethnic differences in drug disposition and response: Review of recently approved drugs Clin Pharma and Therapeutics 2015 97 263 73 10.1002/cpt.61 25669658

69 Pierce E 2024 Empowering APs: Integrating diversity into clinical trial strategies and enhancing research outcomes JADPRO Insight Forum

70 US Food and Drug Administration Conducting clinical trials with decentralized elements 2024 Available https://www.fda.gov/regulatory-information/search-fda-guidance-documents/conducting-clinical-trials-decentralized-elements

71 WCG Clinical Clinical research site challenges survey report 2023 Available https://www.wcgclinical.com/insights/2023-clinical-research-site-challenges-survey-report

72 Sun G Dizon DS Szczepanek CM et al Crisis of the Clinical Trials Staff Attrition After the COVID-19 Pandemic JCO Oncol Pract 2023 19 533 5 10.1200/OP.23.00152 37285550 PMC10424897

73 Braun-Inglis C Williams EL Macchiaroli A et al Better Late Than Never: Fully Incorporating Oncology Advanced Practice Providers Into Cancer Clinical Trials JCO Oncol Pract 2022 18 729 32 10.1200/OP.22.00224 35960907 PMC9653202

74 Liakou CI Kamat A Tang DN et al CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients Proc Natl Acad Sci U S A 2008 105 14987 92 10.1073/pnas.0806075105 18818309 PMC2567480

75 Brahmer JR Drake CG Wollner I et al Phase I Study of Single-Agent Anti–Programmed Death-1 (MDX-1106) in Refractory Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates JCO 2010 28 3167 75 10.1200/JCO.2009.26.7609 PMC4834717 20516446

76 Chen AP Sharon E O’Sullivan-Coyne G et al Atezolizumab for Advanced Alveolar Soft Part Sarcoma N Engl J Med 2023 389 911 21 10.1056/NEJMoa2303383 37672694 PMC10729808

77 Cho BC Abreu DR Hussein M et al Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study Lancet Oncol 2022 23 781 92 10.1016/S1470-2045(22)00226-1 35576957

78 Mirza MR Chase DM Slomovitz BM et al Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer N Engl J Med 2023 388 2145 58 10.1056/NEJMoa2216334 36972026

79 Choueiri TK Tomczak P Park SH et al Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma N Engl J Med 2024 390 1359 71 10.1056/NEJMoa2312695 38631003

80 Amaria RN Postow M Burton EM et al Neoadjuvant relatlimab and nivolumab in resectable melanoma Nature New Biol 2022 611 155 60 10.1038/s41586-022-05368-8 PMC9607737 36289334

81 Patel SP Othus M Chen Y et al Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma N Engl J Med 2023 388 813 23 10.1056/NEJMoa2211437 36856617 PMC10410527

82 Wakelee H Liberman M Kato T et al Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer N Engl J Med 2023 389 491 503 10.1056/NEJMoa2302983 37272513 PMC11074923

83 Baetz TD Song X Ernst DS et al A randomized phase III study of duration of anti-PD-1 therapy in metastatic melanoma (STOP-GAP): Canadian Clinical Trials Group study (CCTG) ME.13 JCO 2018 36 10.1200/JCO.2018.36.15_suppl.TPS9600

84 US Food and Drug Administration Optimizing the dosage of human prescription drugs and biological products for the treatment of oncologic diseases 2024 Available https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases