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Abstract This single-arm phase II non-randomised trial (ACTRN12619001265167) evaluated trastuzumab emtansine in solid cancers with HER2 amplification or mutation detected by comprehensive genomic profiling. The primary objective was objective response (OR), while secondary objectives included the time to progression (TTP) on study to TTP on prior therapy ratio, progression-free survival (PFS) and overall survival (OS). The cohort included 16 tumours with HER2 mutations (group 1) and 16 with HER2 amplification (group 2). After 17 months median follow-up, ORs occurred in 19% of group 1 (1 salivary gland carcinoma (SGC), 2 lung cancers) and 25% of group 2 (3 SGCs, 1 uterine carcinoma). Fourteen of 29 TTP-evaluable patients achieved a TTP ratio ≥1.3, including 10 without an OR. Median PFS and OS were 4.5 (95% CI 2.1–7.0) and 18.2 months (95% CI 8.1-not reached) respectively. Trastuzumab emtansine showed modest ORs and a favourable change in disease trajectory in select HER2-altered solid cancers.

Objective We study how clinical and socioeconomic factors influence colorectal cancer (CRC) costs for patients and Medicare in Australia. The study seeks to extend the limited Australian literature on CRC costs by analysing comprehensive patient-level medical services and pharmaceutical cost data.Design, setting and participants Using the Victorian Cancer Registry, we identified all patients in Victoria who were diagnosed with CRC from 2010 to 2019 and extracted their linked 2010–2021 Medicare data. This data includes expenses from the Pharmaceutical Benefits Scheme and Medicare Benefits Schedule services. We examined variables such as disease stage, CRC type, molecular profile, metastasis status and demographics (eg, age, birth country, socioeconomic level via the SEIFA index, and native language). We applied descriptive and log-linear multivariate regression analyses to explore patient and Medicare costs related to CRC treatment.Results Costs significantly rise with advanced cancer stages, especially on medication costs. Patients’ average out-of-pocket (OOP) expenses are roughly $A441 per year. Key cost influencers are gender, age and socioeconomic status. On average, males incur 13.5% higher annual costs, a significantly larger OOP expense, than females. Compared with patients aged 50 or below, there is a 7.1% cost increase for individuals aged 50–70 and an 8.8% decrease post-70, likely reflecting less intensive treatment for the elderly. Socioeconomic factors show a clear gradient. Wealthier areas experience higher costs, especially among native English speakers. Costs also vary based on cancer’s anatomical location and specific genetic mutations.Conclusion The research highlights that CRC treatment expenses for patients and Medicare differ considerably due to factors such as diagnostic stage, demographics, anatomical location of the tumour and mutations. These cost variations lead to concerns about healthcare equality and decision-making autonomy. Policymakers may need to focus on early detection, increased support for advanced-stage patients, gender-sensitive healthcare, and equitable access to treatment across different socioeconomic groups.

Abstract Metastatic BRAF V600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAFV600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. We have found that a limitation of Enc+Cet treatment is the failure to efficiently induce apoptosis in BRAF V600E CRCs, despite inducing expression of the pro-apoptotic protein BIM and repressing expression of the pro-survival protein MCL-1. Here, we show that BRAF V600E CRCs express high basal levels of the pro-survival proteins MCL-1 and BCL-XL, and that combining encorafenib with a BCL-XL inhibitor significantly enhances apoptosis in BRAF V600E CRC cell lines. This effect was partially dependent on the induction of BIM, as BIM deletion markedly attenuated BRAF plus BCL-XL inhibitor-induced apoptosis. As thrombocytopenia is an established on-target toxicity of BCL-XL inhibition, we also examined the effect of combining encorafenib with the BCL-XL -targeting PROTAC DT2216, and the novel BCL-2/BCL-XL inhibitor dendrimer conjugate AZD0466. Combining encorafenib with DT2216 significantly increased apoptosis induction in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAF V600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-XL inhibition significantly enhances apoptosis in pre-clinical models of BRAF V600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients.

The Ph1 oncology trial landscape is evolving in response to advances in understanding of cancer biology, novel drug discovery platforms, and therapeutic modalities. To uncover emerging trends in oncology drug development, we identified 7,061 solid tumour Ph1 trials (2009–2021) from clinicaltrials.gov to determine the numbers of trials commenced, therapeutic classes, combinations, tumour streams, and geographical distribution. Ph1 oncology trials increased by an average of 5.2 %/year. There was a significant relative increase in the number of immunotherapy studies and a significant relative decrease in trials containing chemotherapy. Between 2009 and 2021, multi-agent combination trials outnumbered single-agent trials and single-class trials outnumbered multimodal combination trials. The proportion conducted in the Asia-Pacific significantly increased. Multiregional trials decreased during the COVID-19 pandemic, reducing projected trial numbers in Asia-Pacific and Europe whilst increasing single-region trials in North America. Further study is required to track recovery post-pandemic, and the emergence of novel modalities (e.g. ADCs and cellular therapies).

Abstract NTRK gene fusions are rare somatic mutations found across cancer types with promising targeted therapies emerging. Healthcare systems face significant challenges in integrating these treatments, with uncertainty in prevalence and optimal testing methods to identify eligible patients. We performed a systematic review of NTRK fusion prevalence to inform efficient diagnostic screening and scale of therapeutic uptake. We searched Medline, Embase and Cochrane databases on 31/03/2021. Inclusion criteria were studies reporting fusion rates in solid tumours, English language, post-2010 publication and minimum sample size. Critical appraisal was performed using a custom 11-item checklist. Rates were collated by cancer type and pooled if additional synthesis criteria were met. 160 studies were included, with estimates for 15 pan-cancer and 429 specific cancer types (63 paediatric). Adult pan-cancer estimates ranged 0.03–0.70%, with higher rates found in RNA-based assays. In common cancers, rates were consistently below 0.5%. Rare morphological subtypes, colorectal microsatellite instability, and driver mutation exclusion cancers had higher rates. Only 35.6% of extracted estimates used appropriate methods and sample size to identify NTRK fusions. NTRK fusion-positive cancers are rare and widely distributed across solid tumours. Small-scale, heterogeneous data confound prevalence prediction. Further large-scale, standardised genomic data are needed to characterise NTRK fusion epidemiology.

Abstract Background Activated immune cells (IC) in the tumor microenvironment (TME) are critical for anti-tumor efficacy. Greater understanding of the dynamic diversity and crosstalk between IC is needed to clarify their association with immune checkpoint inhibitor efficacy. Methods Patients from three tislelizumab monotherapy trials in solid tumors (NCT02407990, NCT04068519, NCT04004221) were retrospectively divided into subgroups by CD8+ T-cell and macrophage (Mφ) levels, assessed via multiplex immunohistochemistry (mIHC; n = 67) or gene expression profiling (GEP; n = 629). Results A trend of longer survival was observed in patients with both high CD8+ T-cell and Mφ levels versus other subgroups in the mIHC analysis (P = 0.11), which was confirmed with greater statistical significance in the GEP analysis (P = 0.0001). Co-existence of CD8+ T cells and Mφ was coupled with elevated CD8+ T-cell cytotoxicity, T-cell trafficking, MHC class I antigen presentation signatures/genes, and enrichment of the pro-inflammatory Mφ polarization pathway. Additionally, a high level of pro-inflammatory CD64+ Mφ density was associated with an immune-activated TME and survival benefit with tislelizumab (15.2 vs. 5.9 months for low density; P = 0.042). Spatial proximity analysis revealed that closer proximity between CD8+ T cells and CD64+ Mφ was associated with a survival benefit with tislelizumab (15.2 vs. 5.3 months for low proximity; P = 0.024). Conclusions These findings support the potential role of crosstalk between pro-inflammatory Mφ and cytotoxic T cells in the clinical benefit of tislelizumab. Trial registration NCT02407990, NCT04068519, NCT04004221.

Abstract Background Mesenchymal chondrosarcoma (MCS) is an ultra‐rare sarcoma that follows a more aggressive course than conventional chondrosarcoma. This study evaluates prognostic factors, treatments (surgery, chemotherapy, and radiation), and outcomes in an Australian setting. Methods We collected demographics, clinicopathological variables, treatment characteristics, and survival status from patients with MCS registered on the national ACCORD sarcoma database. Outcomes include overall survival (OS) and progression‐free survival (PFS). Results We identified 22 patients with MCS between 2001–2022. Median age was 28 (range 10–59) years, 19 (86%) had localised disease at diagnosis of whom 16 had surgery (84%), 11 received radiation (58%), and 10 chemotherapy (53%). Ten (52%) developed recurrence and/or metastases on follow‐up and three patients with initial metastatic disease received surgery, radiation, and chemotherapy. At a median follow‐up of 50.9 (range 0.4–210) months nine patients had died. The median OS was 104.1 months (95% CI 25.8–182.3). There was improved OS for patients with localised disease who had surgical resection of the primary (p = 0.003) and those with ECOG 0–1 compared to 2–3 (p = 0.023) on univariate analysis. Conclusions This study demonstrates contemporary Australian treatment patterns of MCS. The role of chemotherapy for localised disease remains uncertain. Understanding treatment patterns and outcomes help support treatment decisions and design of trials for novel therapeutic strategies.

Background Programmed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab.Methods In this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety.Results Objective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (≥15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported.Conclusions Cosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile.Trial registration number NCT03212404.

Li et al. report outcomes from the atezolizumab/isatuximab arm of the phase Ib/II MORPHEUS-CRC trial in patients with metastatic colorectal cancer. In addition, the authors leverage historical control data from the phase III IMblaze370 study to provide more precise treatment effect estimates.

Desmoid tumors (aggressive fibromatosis) are soft tissue mesenchymal tumors that can be locally invasive and life-threatening. Depending on the location, these tumors are often unresectable or tend to recur after surgery. To date, there are no approved systemic therapies for desmoid tumors. These tumors typically harbor mutations in the β-catenin oncogene CTNNB1 or the tumor suppressor gene adenomatous polyposis coli, resulting in constitutive activation of the WNT pathway. The Notch pathway is part of the underlying cause for desmoid tumor development, possibly due to crosstalk with the WNT pathway, providing a rationale for Notch inhibition as a therapeutic strategy. The gamma secretase activation of the Notch receptor can be targeted with investigational gamma secretase inhibitors. In this case report, we follow the course of 2 patients with desmoid tumors treated with the highly potent, parenterally administered investigational gamma secretase inhibitor AL101, resulting in long-lasting responses. Case 1 reports on a patient with a mesenteric desmoid tumor who participated in a phase 1 trial and then transitioned into a compassionate use program; Case 2 reports on a patient with recurrent pelvic tumors receiving AL101 through a compassionate use program. After tumor progression on other systemic therapies, Cases 1 and 2 had confirmed partial responses (41% and 60% maximal tumor size decrease from baseline) recorded after 1.0 and 1.6 years of treatment with AL101, with a duration of response of 8.6+ and 2.6+ years, respectively. Also, in a phase 1 study of AL102, a potent orally administered gamma secretase inhibitor that shares structural features with AL101, a patient with a desmoid tumor was noted to have tumor shrinkage. Formal clinical testing of AL102 for the treatment of patients with desmoid tumors that are not amenable to surgery or are refractory to/recurrent from other prior therapies is currently underway.

Background and purpose — The ENLIVEN trial showed that, after 25 weeks, pexidartinib statistically significantly reduced tumor size more than placebo in patients with symptomatic, advanced tenosynovial giant cell tumor (TGCT) for whom surgery was not recommended. Here, we detail the effect of pexidartinib on patient-reported physical function and stiffness in ENLIVEN. Patients and methods — This was a planned analysis of patient-reported outcome data from ENLIVEN, a double-blinded, randomized phase 3 trial of adults with symptomatic, advanced TGCT treated with pexidartinib or placebo. Physical function was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS)-physical function (PF), and worst stiffness was assessed using a numerical rating scale (NRS). A mixed model for repeated measures was used to compare changes in PROMIS-PF and worst stiffness NRS scores from baseline to week 25 between treatment groups. Response rates for the PROMIS-PF and worst stiffness NRS at week 25 were calculated based on threshold estimates from reliable change index and anchor-based methods. Results — Between baseline and week 25, greater improvements in physical function and stiffness were experienced by patients receiving pexidartinib than patients receiving placebo (change in PROMIS-PF = 4.1 [95% confidence interval (CI) 1.8–6.3] vs. –0.9 [CI −3.0 to 1.2]; change in worst stiffness NRS = –2.5 [CI −3.0 to −1.9] vs. –0.3 [CI −0.9 to 0.3]). Patients receiving pexidartinib had higher response rates than patients receiving placebo for meaningful improvements in physical function and stiffness. Improvements were sustained after 50 weeks of pexidartinib treatment. Interpretation — Pexidartinib treatment provided sustained, meaningful improvements in physical function and stiffness for patients with symptomatic, advanced TGCT.

Abstract While several resources exist that interpret therapeutic significance of genomic alterations in cancer, many regional real-world issues limit access to drugs. There is a need for a pragmatic, evidence-based, context-adapted tool to guide clinical management based on molecular biomarkers. To this end, we have structured a compendium of approved and experimental therapies with associated biomarkers following a survey of drug regulatory databases, existing knowledge bases, and published literature. Each biomarker-disease-therapy triplet was categorised using a tiering system reflective of key therapeutic considerations: approved and reimbursed therapies with respect to a jurisdiction (Tier 1), evidence of efficacy or approval in another jurisdiction (Tier 2), evidence of antitumour activity (Tier 3), and plausible biological rationale (Tier 4). Two resistance categories were defined: lack of efficacy (Tier R1) or antitumor activity (Tier R2). Based on this framework, we curated a digital resource focused on drugs relevant in the Australian healthcare system (TOPOGRAPH: Therapy Oriented Precision Oncology Guidelines for Recommending Anticancer Pharmaceuticals). As of November 2020, TOPOGRAPH comprised 2810 biomarker-disease-therapy triplets in 989 expert-appraised entries, including 373 therapies, 199 biomarkers, and 106 cancer types. In the 345 therapies catalogued, 84 (24%) and 65 (19%) were designated Tiers 1 and 2, respectively, while 271 (79%) therapies were supported by preclinical studies, early clinical trials, retrospective studies, or case series (Tiers 3 and 4). A companion algorithm was also developed to support rational, context-appropriate treatment selection informed by molecular biomarkers. This framework can be readily adapted to build similar resources in other jurisdictions to support therapeutic decision-making.

Abstract Background Surveillance imaging is used to detect local and/or distant recurrence following primary treatment of localised soft tissue sarcoma (STS), however evidence supporting optimal surveillance modality or frequency is lacking. We used prospectively collected sarcoma data to describe current surveillance imaging practice in patients with AJCC stage II and III extremity STS and evaluate its cost-effectiveness. Methods From three selected Australian sarcoma referral centres, we identified patients with stage II and III extremity STS treated between 2009 and 2013. Medical records were reviewed to ascertain surveillance imaging practices, including modality, frequency and patient outcomes. A discrete event simulation model was developed and calibrated using clinical data to estimate health service costs and quality adjusted life years (QALYs) associated with alternative surveillance strategies. Results Of 133 patients treated for stage II and III extremity STS, the majority were followed up with CT chest (86%), most commonly at 3-monthly intervals and 62% of patients had the primary site imaged with MRI at 6-monthly. There was limited use of chest-X-ray. A discrete event simulation model demonstrated that CT chest screening was the most cost effective surveillance strategy, gaining additional QALYs at a mean incremental cost of $30,743. MRI alone and PET-CT alone were not cost-effective, whilst a combined strategy of CT + MRI had an incremental cost per QALY gained of $96,556. Conclusions Wide variations were observed in surveillance imaging practices in this high-risk STS cohort. Modelling demonstrated the value of CT chest for distant recurrence surveillance over other forms of imaging in terms of cost and QALYs. Further work is required to evaluate cost-effectiveness in a prospective manner.

Background The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors.Methods Patients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab’s safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay.Results Between May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1–2 severity; anemia (4.9%) was the most common grade 3–4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials.Conclusions Tislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies.Trial registration number NCT02407990.

Abstract Immune checkpoint inhibitors (ICIs) induce a durable response in a wide range of tumor types, but only a minority of patients outside these ‘responsive’ tumor types respond, with some totally resistant. The primary predictor of intrinsic immune resistance to ICIs is the complete or near‐complete absence of lymphocytes from the tumor, so‐called immunologically cold tumors. Here, we propose two broad approaches to convert ‘cold’ tumors into ‘hot’ tumors. The first is to induce immunogenic tumor cell death, through the use of oncolytic viruses or bacteria, conventional cancer therapies (e.g. chemotherapy or radiation therapy) or small molecule drugs. The second approach is to target the tumor microenvironment, and covers diverse options such as depleting immune suppressive cells; inhibiting transforming growth factor‐beta; remodelling the tumor vasculature or hypoxic environment; strengthening the infiltration and activation of antigen‐presenting cells and/or effector T cells in the tumor microenvironment with immune modulators; and enhancing immunogenicity through personalised cancer vaccines. Strategies that successfully modify cold tumors to overcome their resistance to ICIs represent mechanistically driven approaches that will ultimately result in rational combination therapies to extend the clinical benefits of immunotherapy to a broader cancer cohort.

Abstract Objectives Tumor‐infiltrating lymphocytes (TIL), particularly CD8+ TILs in patients with colorectal cancer (CRC), are highly prognostic in the early‐disease stages (I‐II). In metastatic disease (stage IV; mCRC), their influence is less well defined. It has presumably failed to contain tumor cells to the primary site; however, is this evident? We explored the prognostic impact of TILs at the primary site in patients who presented de novo with mCRC. Methods Treatment‐naïve patients (109) with mCRC were assessed for CD8+ TILs and PD‐L1 expression. Microsatellite instability (MSI) was evaluated by IHC for PMS2 and MSH6 proteins and/or by PCR using the Bethesda panel. Results Microsatellite instability‐high tumors had significantly more CD8+ TILs, with no significant survival advantage observed between MSI‐H and microsatellite stable (MSS) tumors (12 vs 19 months, P = 0.304). TIL density for all cases had no impact on OS (low: 20 vs high: 13 months, P = 0.426), while PD‐L1 of 1% or higher was associated with reduced mean survival (9.6 vs 18.9 months; P = 0.038). MSI‐H tumors and associated immune cells had higher PD‐L1 expression than in MSS cases. A positive correlation between PD‐L1 on immune cells and CD8+ve TILs was found. A subset of MSS tumors had relatively high TILs approximating that of MSI‐H tumors. Conclusion In contrast to early‐stage CRC, the immune response in primary tumors of patients with de novo mCRC does not appear to influence survival. A subgroup of MSS tumors was identified with increased TILs/PD‐L1 comparable to MSI‐H tumors, traditionally not be considered for immune checkpoint blockade and perhaps should be.

The success of monoclonal antibody (mAb) therapeutics have increased pharmaceutical investment in mAb production, which has led to a greater demand of technologies to efficiently characterize these biotherapeutics. The large size and heterogeneity of mAbs require the measurement of multiple critical quality attributes (CQAs) during production. The current workflow to measure CQAs of antibodies involves multiple one-dimensional liquid chromatography methods, including Protein-A (ProA), ion-exchange (IEX), reversed-phase, size exclusion (SEC), hydrophilic interaction, and hydrophobic interaction (HIC). Recent advances in commercial two-dimensional liquid chromatography (2D-LC) affords an opportunity to perform two separations at once to measure multiple CQAs in a single assay. Here, we describe the development of a 2D ProA–SEC method using entirely commercially available instrumentation. Each individual separation and the transfer of material between dimensions were optimized to develop a method that measures titer and aggregation of a target antibody from harvested cell culture fluid in under 5 min. We determined the effects of each parameter of the method on mAb recovery and stability, as well as speed, robustness, resolution, and accuracy of the aggregate amount detected in the second dimension (2D). While there are still sources of error caused by hardware limitations, our rapid ProA-SEC method is an effective screening tool with a significant throughput advantage over previously described methods. Additionally, this work serves as a basis for developing other 2D-LC methods with ProA as the first dimension (1D) separation coupled with different 2D separation, such as ProA-IEX and ProA-HIC.

Background: MYB is a transcription factor that is overexpressed in colorectal cancer (CRC) and also a driver mutation in adenoid cystic carcinoma (AdCC). Therefore, the MYB protein is an ideal target to vaccinate against to aid recruitment of tumour infiltrating lymphocytes (TILs) against these tumours. The Peter MacCallum Cancer Centre (Melbourne, Australia) has engineered a DNA vaccine, TetMYB, based on the pVAX1 plasmid vector carrying a fusion construct consisting of the universal tetanus toxin T-cell epitopes flanking an inactivated MYB gene. Methods: This prospective first-in-human phase I single-arm multi-centre clinical trial involves patients with metastatic CRC or AdCC. Stage 1 will evaluate the safety profile of escalating doses of TetMYB vaccine, given sequentially and in combination with an anti-PD-1 inhibitory antibody, to determine the maximum tolerated dose (MTD). Stage 2 will assess the MTD in an expanded cohort. The calculated sample size is 32 patients: 12 in Stage 1 and 20 in Stage 2. The expected total duration of the trial is 3 years with 15 months of recruitment followed by a minimum of 18 months follow-up. Discussion: MYB transcription factor is aberrantly overexpressed in a range of epithelial cancers, not limited to the above tumour types. Based on promising pre-clinical data of vaccine-induced tumour clearance and establishment of anti-tumour memory, we are embarking on this first-in-human trial. If successful, the results from this trial will allow progression to a Phase II trial and validation of this breakthrough immunotherapeutic approach, not only in CRC and AdCC, but other MYB over-expressing cancers. Trial registration: ClinicalTrials.gov ID: NCT03287427. Registered: September 19, 2017. Keywords: Colorectal neoplasms, Adenoid cystic carcinoma, Glandular and epithelial neoplasms, Cancer vaccine, Immunotherapy, Immune checkpoint therapy