Phase I trials of single-agent new drugs in head and neck cancer: a scoping review

Introduction

General considerations on the design methods of phase I clinical trials

Phase I trials represent a first critical step in drug development. Given that the evolution path of a drug is significantly influenced by data derived from phase I trials, a rigorous design and meticulous conduct are crucial. Typically, phase I trials are single-arm and non-randomized, characterized by a small sample size. The main goal of these trials is to establish a recommended dose for subsequent investigations of the experimental agent, named as recommended phase 2 dose (RP2D) (1,2).

The design of phase I trials includes a dose escalation phase that may allow an intra-patient dose escalation and an expansion cohort aiming to increase confidence in the safety and appropriateness of the defined final dose. Expansion cohorts may also offer evidence of early antitumor activity. One of the main goals of a phase I design is the definition of dose-limiting toxicity (DLT), referring to toxic effects presumed to be related to the drug and considered unacceptable due to their severity, thereby limiting further dose escalation. The highest dose level administered during dose escalation at which a critical number of DLT is observed, is referred to the maximum tolerated dose (MTD) and the identification of the MTD will further help to define the RP2D (3,4). While the traditional 3+3 dose escalation design has been widely utilized in many studies, innovative methodological strategies have emerged in recent decades to tackle innovations in oncological therapeutics (5,6).

An overview of head and neck cancers (HNCs)

HNC represents the seventh most common cancer worldwide, accounting for the 4.5% of all new cancer diagnosis with 900,000 new diagnoses and 450,000 deaths each year. Furthermore, the global incidence of HNC has increased over the last years, particularly in younger patients, with a predicted 30% annual incidence rise by 2030 (7,8). Several risk factors are associated with the development of HNC, including tobacco use and alcohol consumption, human papillomavirus (HPV) infection, poor oral hygiene, and exposure to certain occupational hazards (such as wood dust).

Treatment strategies for HNC often involve a multidisciplinary approach and may include surgery, radiotherapy and chemotherapy, or a combination of these, for locally advanced HNC, whereas in the recurrent/metastatic (R/M) setting, immune checkpoint inhibitors (ICIs) have been introduced (9). Despite advances in treatment modalities (10-13), HNC can be difficult to manage due to their complex anatomy, potential for locoregional spread, and the impact of treatment on essential functions such as speech, swallowing, and breathing. The prognosis of HNC remains poor and treatments are still associated to acute and long-term toxicities. Moreover, due to their aggressive behavior and anatomical and molecular heterogeneity, head and neck squamous cell carcinoma (HNSCC) poses a significant challenge in drug development.

Early phase trials in patients with HNC

Historically, patients with HNC have been enrolled into early phase clinical trials among patients affected by other solid tumors. More recently, some studies have been designed specifically for HNSCC while rare histotypes of HNC such as salivary glands, nasopharynx and paranasal sinuses are still heterogeneously integrated in these trials.

The traditional method of drug development in oncology goes from phase I, to phase II, to randomized phase III studies. However, some recent drugs approvals in HNC were based on the results of single arm phase II studies (14-16), highlighting the value of phase I trials as a crucial step in the investigation of new drugs in patients with HNC. The majority of reviews of published phase I trials includes key aspects of methodological designs of studies enrolling patients affected by various solid tumors without focusing on the HNC disease. Additionally, considering the distinctive characteristics of HNC regarding its molecular and immune profile, the particular vulnerability of its population, and the specific treatment-related toxicities linked to anatomical tumor localization (17,18), it could be argued that focusing on phase I trials specifically tailored to HNC is more justified. This would involve a detailed analysis of the drug development trajectory within this peculiar setting.

Here, we present a review of first-in-human phase I trials evaluating treatments administered as single agents, specifically conducted in patients with HNC. Our aim is to highlight the main features of these clinical trials including the agents investigated and their main properties, the design characteristics, safety and activity results. Furthermore, a review of current ongoing phase I trials in HNC is provided. We present this article in accordance with the PRISMA-ScR reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-24-33/rc).

Methods

Search strategy

According to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) process (19), a comprehensive review of the PubMed database was undertaken for literature published before November 2023, without publication year restrictions. We conducted the search using a combination of key terms and medical subject heading [MeSH Terms]. The search strategy is summarized with the following search string: “(phase I) AND (head and neck)”, and was conducted on 30^th November 2023. To ensure exhaustiveness, we also performed a search from the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO) and American Association for Cancer Research (AACR) websites. The abstracts identified through this search were screened and evaluated using identical study selection criteria.

Reference lists from screened articles were also searched. The cross-references from selected studies were further searched for additional articles. Articles identified through this search were screened and evaluated using identical study selection criteria. Titles and abstracts were screened for relevance by the first author of this study, while disagreements were solved through discussion with the other authors.

Additionally, a search on clinicaltrials.gov registry for current recruiting phase I clinical trials evaluating single agent treatments specifically conducted in HNC, is provided: the advanced search function on the Website was utilized for the term “head and neck cancer” and was refined by applying the following options available on the search page, “recruiting” and “phase I” and “interventional” and “adults 18 years or older”. Trials with sites different from head and neck, non-anticancer drugs, combination treatments and pediatric population were excluded. Screening of all these data is conducted by the first author. This search aimed to identify ongoing studies that focus solely on single-agent therapies in adult HNC patients, ensuring specificity about the current research trends in HNC reflecting this review’s objectives.

Inclusion and exclusion criteria

Studies fulfilling the following criteria were included: (I) phase I clinical trials reporting dose escalation findings; (II) trials evaluating specifically patients with HNC including squamous cell cancers (SCCs) of oral cavity, oropharynx, larynx, hypopharynx, salivary gland cancers, nasopharynx, paranasal sinus; (III) single agent treatments; (IV) studies involving adult patients; (V) written in English. Exclusion criteria were: (I) trials lacking a dose escalation phase, involving drug-drug interactions, pharmacokinetic or bioavailability studies as well as window of opportunity trials; (II) investigations on combination treatments (drugs administered before radiotherapy for locally advanced disease were analyzed); (III) trials related to esophageal and thyroid cancers; (IV) trials not reporting a clear description of cancer histology (i.e., studies including “other” solid tumors or not being specific of head and neck site); (V) not anticancer drugs including imaging agent or supportive therapy; (VI) non-original research articles, such as review articles, conference proceedings, editorials and book chapters; (VII) interim analysis; (VIII) evaluation involving pediatric patients.

In this work, we decided to exclude trials not providing dose-escalations results as the primary purpose of phase I is to determine the safety and appropriate dosage range of a treatment through dose escalation and without this data, the studies do not contribute significantly to the review’s objectives.

In this study, phase I trials evaluating combination treatments were excluded because they complicate the assessment of the individual effects and safety profiles of the treatments. Indeed, combination studies introduce multiple variables, making it difficult to isolate the impact of each treatment. For the purposes of the review, it was essential to focus on studies that provided clear data on single agent treatments. However, treatments administered before radiotherapy were included because they may represent a novel therapeutic strategy and could significantly impact the overall effectiveness and outcomes of the radiotherapy in a curative setting.

Data extraction

One author (D.M.F.) retrieved information from the eligible articles following the inclusion and exclusion criteria, and data were collected on a standardized data sheet that included: PMID of the publication, class of drugs, name of drugs, mechanism of action, administration modality, histology, localization of HNC, setting of treatment (neoadjuvant vs adjuvant vs. locally advanced vs. first line for R/M vs second line or more than second line treatment for R/M), number of patients included, number of dose levels, DLT, MTD, RP2D, safety [treatment-related adverse events (TRAEs) ≥3], overall response rate (ORR), other results of activity.

The results in this database were verified by other authors (G.M., E.B., R.S., and E.B.) through a step-by-step control process. The final review was conducted by the last author. Any disagreements regarding article inclusion and data extraction during this process were resolved collaboratively by all the authors.

Results

Study selection

In total, our search identified 1,134 articles including 902 from databases and 232 from websites. The initial screening from the database articles removed duplicated/retracted/in erratum (n=31) papers and records not dealing directly with the investigated issue (n=271) and for other reasons (n=12). Next, we excluded 212 articles because they were not inherent to the topic and 376 reports were sought for retrieval. Furthermore, 105 full text articles were read and then assessed for eligibility. Among these, some articles were excluded for describing tumors without a specific focus on HNC (n=29), for evaluating combination treatment strategies (n=34), for presenting interim analyses (n=1) and for other reasons, such as for reporting only translational results or not reporting dose escalation findings (n=18). Although one selected study evaluated a chemotherapeutic agent in patients with HNC and anal cancers, we included it in our analysis because 31 patients out of 43 were affected by HNC and results of safety and activity were clearly and specifically reported for this population. Based on the website search, 18 reports were evaluated for eligibility, with 12 being excluded. Finally, the review was performed on a total of 29 studies. The flowchart of the systematic search is shown in Figure 1.

Figure 1 The PRISMA flowchart of the review.

Characteristic of the selected studies

The 29 eligible articles were published between 1994 and 2023 for a total of 741 (range, 7–93) patients included. Specifically, between 1994 and 2003 (n=10), 2004–2013 (n=9), 2014–2023 (n=10). The significant majority (90%) enrolled patients with SCC, whereas only three trials encompassed adenoid cystic carcinoma, sarcoma and ameloblastic carcinoma. Concerning the tumor subsite, most of trials (72%) included patients with various localizations of HNSCC while only 8 trials (27%) were specifically focused on a defined subsite of head and neck. In detail, one trial was focused on HPV-positive SCC, one on hypopharynx, one on hypopharynx/larynx, three on nasopharyngeal cancer (NPC), one on oral cavity, one on oral cavity and oropharynx. The R/M setting was predominant across the selected trials (86%). Regarding the class of drugs, most of the articles examined immunotherapeutic agents (n=11, 38%), including three ICIs, seven vaccine-based treatments and one immunocytokine. The second most represented class of drug was targeted therapy (n=7, 24%), followed by cytotoxic agents (n=6, 21%) and others (n=5, 17%) containing a nanoparticle (n=1), gene therapy (n=1), fusion proteins (n=2) and a modulator of gene expression (n=1). One trial with an antibody drug conjugate (ADC) is also included.

Overview of the selected studies categorized by drug class

The main characteristics and preliminary activity results of the 29 phase I trials evaluating cytotoxic agents, immunotherapeutic agents, ADCs, targeted agents and other agents in head and neck oncology are presented below and reported in the respective tables.

Cytotoxic agents

A total of 6 trials (20-25), including 148 patients, evaluated cytotoxic agents: two anthracyclines as pegylated liposomal doxorubicin, two taxanes (paclitaxel encapsulated in cationic liposomes and paclitaxel incorporated in albumin nanoparticles), and two cisplatin-based therapy (a pegylated liposomal cisplatin and a supradose cisplatin intra-arterial infusions) (Table 1). According to the modality of administration, three drugs were injected intravenously, two intraarterially, and one intratumorally. Most of tumor localizations explored were HNSCC, including two studies which also evaluated NPC, while one study was limited to hypopharynx. For one trial investigating pegylated liposomal cisplatin, a lack of efficacy of this compound is reported and for paclitaxel encapsulated in cationic liposomes an absence of response was reported while the other compounds showed signals of activity.

Immunotherapy

Immunotherapeutic agents were investigated in 11 trials (26-36) designed specifically for HNC for a total of 344 patients: three ICIs, seven vaccine-based treatments, and one immunocytokine (Table 2). The HNC site explored in eight trials was HNSCC (one also encompassing NPC) while in two studies was limited to NPC. For one trial testing the CUE 101, the site was limited to HPV-related HNSCC. Five drugs were investigated in locoregional recurrent disease and given by an intratumoral administration. One drug administered by subcutaneous injection was tested in patients with NPC in remission after primary treatment. The other agents were tested in R/M disease. The study testing the GL-0810 (HPV16) and GL-0817 (MAGE-A3) vaccines was closed early due to insufficient accrual. Globally, these drugs showed a good safety profile and for certain drugs promising responses are revealed.

ADC

The ADC investigated in 32 patients with R/M HNSCC was bivatuzumab mertansine (37) which is a highly potent antimicrotubule agent coupled to a monoclonal antibody against CD44v6. Its development, however, was abandoned because in a parallel trial a patient with esophageal carcinoma died from toxic epidermal necrolysis.

Targeted agents

Seven targeted agents including two anti-epithelial growth factor receptor (EGFR) therapy, one member of the inhibitors of apoptosis (IAP) family, one anti-CD44v6 humanized monoclonal antibody, one anti-Epstein Barr nuclear antigen, one anti-stemness kinase inhibitor, and one anti-fibroblast growth factor receptors (FGFRs) were evaluated for a total of 136 patients enrolled (38-44) (Table 3). In two trials investigating an anti-EGFR and the IAP member, HNSCC sites were limited to larynx/hypopharynx and to oral cavity, respectively. The other trials encompassed multiple sites and histologies. For one drug, the administration modality was represented by intratumoral delivery for a recurrent disease. Globally, the median ORR was poor and under 10%. However, in the trial evaluating the anti-FGFR, gunagratinib, a response rate was observed in 3 out of 9 harboring FGF/FGFR gene alterations.

Other agents

Four novel agents including one nanoparticle, one therapeutic gene, one recombinant fusion protein and one modulator of gene expression were investigated for a total of 81 patients (45-48) (Table 4). The NBTXR3 was a first-in-class radioenhancer nanoparticle designed to enhance the effects of radiotherapy. The therapeutic gene was an EGFR antisense DNA therapy under U6 promoter control. The fusion protein was VB4-845 which is an anti-epithelial cell adhesion molecule (EpCAM) recombinant fusion protein while the modulation of gene expression of all-trans retinoic acid was mediated through retinoid binding to specific nuclear retinoid receptors. Modalities of administration were intratumoral injection for three drugs in the locally advanced or recurrent setting and oral route for all-trans retinoic acid agents across all stages of disease. In a trial investigating the recombinant fusion protein VB4-845, an ORR of 71% was observed among patients with clinically evaluable EpCAM-positive tumors. These investigating drugs appear promising in terms of response and good tolerability profile.

Analysis of DLT across all trials

DLT was undefined in the reports of 8 trials (27%). Among trials that reported the presence of at least one DLT (n=7), its definition was variable ranging from hematologic toxicity only in two trials and also non-hematologic toxicity in five trials. Hematologic DLT was characterized as grade 4 neutropenia in one trial and as grade 4 thrombocytopenia and leukocytopenia in another, involving a cytotoxic agent and a targeted agent, respectively. In a trial of an anti-EpCAM, non-hematologic DLT was defined as grade 3 elevated liver enzymes. In two trials evaluating the pegylated liposomal doxorubicin (Caelyx) and supradose cisplatin infusion, grade 3 stomatitis and severe electrolyte loss of sodium, magnesium and potassium, were observed as dose-limiting, respectively. One trial focusing on IL-2 administered at the last dose level exhibited grade 3 fever, cardiac toxicity, and hypotension considered as DLT. The trial with the ADC, bivatuzumab mertansine, binding to CD44 on skin keratinocytes, reported skin toxicity as DLT. This toxic effect represented the cause of a fatal outcome in a parallel trial (49) so the development program of this compound was stopped. The remaining trials including seven immunotherapeutic agents, three targeted agents, two other agents (in particular, the nanoparticle and the therapeutic gene) and two cytotoxic agents reported no instances of observed DLT.

Analysis of MTD and recommended phase ii dose across all trials

In 9 trials (31%) the MTD was not assessed. The MTD was reached in 50% of trials. For agents where the MTD was not achieved in the absence of DLT and with a wide therapeutic window, the RP2D was established. Notably, only for one cytotoxic agent (pegylated liposomal cisplatin) for which the MTD was not reached, the RP2D was not established due to the drug’s inefficacy. A RP2D was provided in 19 studies. In four trials, the RP2D was equivalent to the MTD, and in three cases, it was defined as one dose level below the MTD. This depends on where the trials are conducted. Indeed, in the United States the RP2D is equivalent to the MTD whereas in Europe and Japan the RP2D is defined at one dose level below the MTD (3).

Nine trials did not recommend a dose for phase 2 testing, primarily due to the drug’s inefficacy or the necessity for further cohort expansion to define the value of the RP2D. A median of four dose escalations (range, 2–35) was required to reach the MTD in all trials. The trial with the targeted agent gunagratinib (ICP-192) had the highest number of dose levels (n=35), while the lowest number (n=2) was reported for two cytotoxic agents (pegylated liposomal doxorubicin and pegylated liposomal cisplatin) and a targeted therapy (survivin-derived peptide, the IAP protein).

Safety evaluation across all trials

Eighteen out of 29 trials (62%) reported at least one grade 3 or 4 TRAE. However, for seven trials, the rates of grade 3 and 4 TRAEs were not entirely assessable from the published data, as they were only partially reported and no clear presentation of AEs for each patient enrolled was provided. The reporting of grade 5 TRAEs rate was not revealed across all eligible trials. Overall, the incidence of grade 3 or higher TRAEs was low (median 7%; range, 0–62%), with 10 trials reporting the absence of these. However, in five trials the rate of grade 3 or higher TRAEs was at least 40%, reaching 62% in the trial with the DNA-hsp65 immunotherapy. Regarding the class of drugs (Figure 2), cytotoxic agents exhibited the highest rate of grade 3 or higher TRAEs while for targeted agents limited rates of toxicity were observed. For “other” class, the TRAEs were clearly reported only in two trials.

Figure 2 Safety and efficacy rate according to class of drugs. ADC, antibody-drug conjugate; TRAEs, treatment-related adverse events; ORR, overall response rate; R/M, recurrent/metastatic.

Efficacy across all trials

Among the 26 publications reporting response rates specifically in patients with HNC, three trials evaluated new agents in the locally advanced setting (including one which encompassed also recurrent disease). For the nanoparticle NBTXR3 and for the chemotherapeutic agent ABI-007 the ORR were very promising (69% and 76%, respectively) while the trial testing the chemotherapy SPI-077 showed lack of efficacy. For the 23 publications in the R/M setting, the median ORR was 12%, while 4 trials (17%) exhibited no overall responses. The low response rate might be attributed to studies evaluating monotherapy agents. The lowest median ORR was reported in trials evaluating targeted agents (median 7%; range, 0–33%) while for the other classes, a median ORR of 29% was observed for two trials investigating a therapeutic gene and a recombinant fusion protein, reporting 29% and 71% respectively (Figure 2).

“Ongoing” phase I trials of single agents in head and neck oncology: current research trends

In an attempt to identify the current trends in head and neck clinical research, we examined recruiting clinical trials evaluating single agent treatments in HNC listed in the ClinicalTrials.gov registry. Of the 304 trials initially identified, we retrieved 20 phase I trials of anticancer drugs administered as monotherapy in patients with HNC. Half of these trials (n=10, 50%) involved immunotherapeutic agents including three vaccine-based treatments, followed by cell therapy (n=5, 25%), targeted agents (n=2, 10%), chemotherapy (n=2, 10%), and ADC (n=1, 5%). Thirteen out of 20 (65%) explored treatments in R/M setting while the remaining in a locally advanced setting or at surgically respectable stages. Most of the studies investigated treatments in HNSCC patients (n=10, 50%), with two trials also encompassing SGCs and NPC, and 5 trials (25%) specifically addressed treatments in NPC. Interestingly, four trials focused on treatments in a highly specific population: two for R/M SGCs (including one only for ACC), while two trials exclusively addressed HPV-positive oropharyngeal cancers. Table 5 reports the main features of these recruiting trials.

Discussion

We performed a review of phase I trials evaluating treatments as single agents, specifically designed for patients with HNC. We identified only 29 phase I trials, published over the last three decades, including a total of 741 patients with HNC. Regarding the tumor subsite, most of published trials comprised patients with different sites of HNSCC and only 8 trials (27%) were focused on a specified subsite of head and neck.

While the inclusion of different histologies is common in phase I trials across various tumor types, it becomes a point of critique when considering more specific HNC-subtype-oriented phase I trials, even for dose-escalation findings. This criticism is particularly pronounced in the context of HNC, given its remarkable heterogeneity and different biological behaviors, according to the peculiar anatomic subtype (50). Interestingly, ongoing phase I trials are showing a tendency to include a more selected population, with 45% of trials specifically designed for a subsite or a particular group (e.g., HPV-positive oropharyngeal cancers). Of note, none of the trials specifically examined the rarer HNC site such as paranasal sinus.

Regarding the drug classes, although the evaluation of immunotherapeutic agents account for the majority of published literature, there is a consistent proportion of trials that investigated cytotoxic agents. On the other hand, when analyzing recruiting trials specifically conducted for patients with HNC, a significant majority is represented by immunotherapeutic agents including vaccine-based treatments and more innovative cell therapies encompassing chimeric antigenic receptor-T (CAR-T)-based treatments. The development of cytotoxic agents declines, with only two trials using this approach. The prevalence of more innovative treatments in the spectrum of ongoing clinical trials underscores the need for enhanced therapeutic alternatives to address the current shortfall in improving the prognosis of HNC patients. The present inclination of focusing investigations on innovative treatments is in line with the trend of other reviews across various cancer types where immunotherapy was predominantly investigated (51,52).

A rigorous design of a phase I is established by a clear and standardized data reporting, in terms of MTD, DLT and RP2D as well as safety and activity results. Determination of the MTD of new experimental agents is the primary objective of phase I clinical trials that ultimately defines the recommended dose for future phase II trials (53). However, there is notable variability in tolerated doses among patients within the same trial, and this variability was not reported in the majority of trials assessed in this work. Additionally, information regarding MTD and DLT was absent in 31% and 27% of studies, respectively, constraining the comprehensive evaluation of research findings (54). Another criticism involves the inconsistency in defining DLT, with variations observed among trials [e.g., the absence of DLT grading according to Common Terminology Criteria for Adverse Events (CTCAE) and/or a detailed definition of the limiting toxicity]. Moreover, none of the studies considered delayed toxicity in the definition of RP2D.

The lack of standardized reporting for the definition of DLT across published trials, especially regarding the number of patients required to exhibit DLT for a dose level to be declared the MTD, is in line with observations made in other reviews of both solid and hematological tumors (55-59). These works emphasize the necessity for a consistent and homogeneous definition of DLT in order to enhance the comprehension of practical implications derived from each study findings.

With regards to safety evaluation, our study revealed relatively low rates of grade 3 or higher TRAEs, with 48% of trials reporting grade 3 or higher TRAEs rates under 10%. These findings demonstrate the relative safety of phase I trial enrolment and are conforming with available literature data (60,61). However, in 20% of publications, the information of grade 3 or higher TRAEs was missing or not clearly systematically reported in the text. This represents a major criticism for the reporting of these trials, given the assessment of safety as the main objective of phase I trials.

Other consideration is represented by the importance of a clear presentation of preliminary efficacy signals. Although the clinical efficacy of an investigational new agent historically may not represent the primary goal in first-in-human phase I trials, it’s increasingly encouraged to report response rate data while the analysis of disease stabilization could suggest caution as an indicator of efficacy of a new treatment even within trials assessing the same tumor type (62). This is consistent with our findings showing that the disease control rate value is reported for a minority of trials whereas the more important results like duration of response is unknown in most of trials. Overall, reported response rates are low and comparable to those usually reported for phase I trials enrolling unselected patients with different types of solid tumors (63-65). However, with the rapid development of newer treatments in oncology including innovative targeted agents, ADC, immunotherapies, more recent reports describe higher response rates closer to 20% (51). It is unclear whether the outcomes of patients included in oncology phase 1 trials, such as response rate and survival, have improved with the refinement of patient selection or the development of innovative investigational agents in recent decades. A recently published work of the National Cancer Institute about phase I trials for solid tumors confirmed that patients who received treatment in disease-specific trials experienced higher response rates and longer survival (63). In our work, the global low response rate and the similar rates between cytotoxic and more innovative treatments such as immunotherapies could rely on the lower efficacy of these agents given as monotherapy.

We acknowledge some limitations of this study. Firstly, we analyzed phase I trials selectively limited to only one tumour type excluding phase I trials recruiting two or more different tumors. Moreover, the safety and efficacy analyses were incomplete in some publications (n=7 and n=3, respectively) and based on inconsistent reporting practices. We included adverse events which were related or possibly related to study drugs, whereas the response rates exhibited significant heterogeneity, with not all response rates being based on RECIST version 1.1. Lastly, this work focused on single-agent treatments. Whilst this contributes to a robust factor of homogeneity in selection, it also poses a limitation by not faithfully representing the categorization of treatments based on drug classes. Nevertheless, our study provides insights into available literature and current trends in phase I trial agents administered as single agents for HNC patients.

Implications for clinical practice and future research

The limited number of phase I trials dedicated to single-agent treatments for HNC highlights a gap in early-phase clinical research. This scarcity suggests a need for more targeted studies to explore the efficacy and safety of potential new treatments for HNC. Future research should aim to consider the heterogeneity of HNC, specifically providing more detailed subgroup analyses for each tumor subsite included in these trials to better understand the differential efficacy and safety. Researchers should also consider integrating biomarkers and other molecular profiling tools to better predict patient response and personalize treatment strategies.

Conclusions

In conclusion, we have provided a comprehensive overview of current evidence into the landscape of dose-escalation phase I trials evaluating single agent treatments, specifically designed for patients with HNC. In the last decades we have assisted to a paradigm shift in U.S. Food and Drug Administration approval of new agents as anticancer therapies based on results from phase I/II trials (66,67). In this context, the inclusion of highly selective population in early phase trials combined with a higher degree of methodological standardization in reporting toxicity and activity results represents the major challenges in the evaluation of experimental drugs in head and neck oncology in future phase I trials. Our study not only highlights the current trends and gaps in the existing literature but also emphasizes the need for more rigorous and targeted phase I trials. These trials are crucial for advancing our understanding of HNC therapies and ultimately improving patient outcomes. The insights gained from our review can guide future research and clinical practice, fostering the development of more effective and personalized treatment strategies for HNC patients.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA-ScR reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-24-33/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-33/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-33/coif). C.L.T. serves as an unpaid editorial board member of Chinese Clinical Oncology from August 2023 to July 2025. C.L.T. participated in Advisory Boards sponsored by Amgen, Astra Zeneca, BMS, Celgene, Merck Serono, MSD, Nanobiotix, Rakuten, GSK, Roche, Seattle Genetics, MaxiVax, and ALX Oncology. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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