Advanced Solid Cancers Research Articles

Fecal microbiota transplantation combined with anti-PD-1 inhibitor for unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor.

105 Background: The gut microbiome is emerging as a key regulator of the immune system during immunotherapy. However, the effect of modulating the gut microbiome in patients (pts) with cancer refractory to immunotherapy remains largely unknown. We aimed to evaluate whether the fecal microbiota transplantation (FMT) could help overcome resistance in pts with advanced solid cancer refractory to anti-PD-(L)1 inhibitors and identify specific commensal bacteria that contribute to the efficacy of FMT (NCT04264975). Methods: This is a prospective, single-arm clinical trial of FMT plus anti-PD-(L)1 inhibitor in pts with advanced solid cancer refractory to anti-PD-(L)1 inhibitors. The key eligibility criteria for donors included ongoing durable complete or partial response ≥ 6 months with anti-PD-(L)1 monotherapy for advanced solid tumors. FMT was performed using colonoscopy, followed by continuation or reintroduction of anti-PD-(L)1 inhibitor until unacceptable toxicity or disease progression. Repeated FMT from the same or different donors was allowed. Results: From Jan. 2019 to Aug. 2020, 13 pts with metastatic gastric cancer (GC) (n=4), esophageal squamous cell carcinoma (ESCC) (n=5), and hepatocellular carcinoma (HCC) (n=4) were enrolled; male (77%), median age=60 yrs (range, 38-76), and median line of prior systemic therapy=3 (range, 2-5). All had confirmed disease progression on nivolumab monotherapy with primary (46.2%) or secondary resistance (53.8%), and underwent FMT with continued nivolumab. There were six FMT donors (HCC [n=4], GC [n=1], ESCC) [n=1], who had maintained (CR; n=4) or (PR; n=2) with nivolumab or pembrolizumab monotherapy. Of the 13 recipients, five showed SD and one achieved PR after FMT with a disease control rate of 46.2% (6/13) and an objective response rate of 7.7% (1/13). Recipient #7 (R7), who had metastatic HCC with primary resistance to nivolumab, initially showed PD to the 1st FMT from donor #1, but achieved PR after the 2nd FMT from donor #5. Clinical response was accompanied by an increase in levels of cytotoxic T cells in the blood and tumor microenvironment, immune cytokines, and the relative abundance of a new species derived from donor #5 showing 97% whole genome nucleotide sequence similarity with Prevotella sp. Marseille-P4119. We isolated this species from feces of R7 and preclinical experiments showed that treatment with this species activated human CD4+ and CD8+ T cells with increased IFN-γ secretion, and suppressed tumor growth in a syngeneic mouse model by enhancing tumor infiltration of cytotoxic T cells. Moreover, the combination treatment with anti-PD-1 and this species reduced the tumor volume more than with anti-PD-1 alone. Conclusions: FMT containing the effective microbiota could overcome resistance to anti-PD-1 inhibitor by modulating the tumor microenvironment in advanced solid cancer pts. Clinical trial information: NCT04264975 .

End-of-life outcomes after implementation of an embedded, criteria-based palliative care consultation service in inpatient oncology.

12121 Background: Specialty palliative care (PC) improves outcomes for patients with advanced cancer, including quality of life and end-of-life (EOL) care utilization. In 2017, the American Society of Clinical Oncology recommended that patients with advanced cancer see specialty PC within 8 weeks of diagnosis. Despite this, inpatient PC referrals exceed outpatient referrals nationwide. Recognizing the importance of earlier PC access, our cancer center implemented a criteria-based PC consultation service in the inpatient oncology setting. We now report pre/post EOL outcomes from this novel care model. Care model: Our center embedded a “Palliative Oncology” consult team on the oncology floor consisting of 1 physician, 1 nurse practitioner (NP), 2 social workers, and 2 spiritual care providers, all with PC specialization. Admitted patients were screened by a floor nurse or PC NP for 2 referral criteria: 1) advanced/metastatic solid cancer, or 2) moderate/severe symptoms. The inpatient oncology team was informed of patients meeting criteria through daily prompting supported by ongoing education. Referrals remained at discretion of the oncology team rather than triggering automatically. Methods: We identified all cancer center decedents with advanced solid cancers who experienced an admission to the oncology floor before (10/1/19-6/30/20) or after (7/1/20-9/30/21) the new model. Six trained abstractors performed chart review. We compared outcomes between patients who died pre- and post-implementation using a t-test (continuous variables) and χ2 test (categorical variables). Results: Of 820 decedents, 186 died pre-intervention and 634 died post-intervention. During the post-intervention period, more decedents saw inpatient PC (72% vs. 59%, p < .001) and outpatient PC (34% vs. 23%, p < .01). Post-intervention decedents had more inpatient PC visits (mean: 11.1 vs. 8.9, p < .05) and had their first PC visit sooner before death (mean: 159 vs. 76 days, p < .001). During the post-intervention period, fewer decedents had ED (41% vs. 52%, p < 0.05), hospital (57% vs. 71%, p < .001), or ICU encounters (17% vs. 25%, p < .01) in the last 30 days of life. For post-intervention decedents, the proportion referred to hospice remained stable (67% vs. 60%, p = .09), but mean hospice length-of-stay increased (36 vs. 22 days, p < .05), as did the proportion who died at home (50% vs. 41%, p < .05). Fewer post-intervention decedents received systemic cancer therapy in the last 14 days of life (5% vs. 9%, p < .05). There were no between-group differences in age at cancer diagnosis, age at death, gender, race/ethnicity, insurance, or primary cancer. Conclusions: A criteria-based “Palliative Oncology” inpatient consult service was associated with earlier, more intense PC and improved EOL quality outcomes, representing a successful effort to enhance PC integration in the inpatient oncology setting.

The lung-immune prognostic index (LIPI) to predict early mortality among patients affected by advanced solid cancers under immune-checkpoint inhibitors treatments.

e14602 Background: The introduction of immune-checkpoint inhibitors (ICI) revolutionized the treatment of several advanced neoplasms. Unfortunately, a considerable rate of patients experiences early death (≤ 90 days). Transversal prognostic factors for early death under ICI single agents or in combinations with other agents are lacking. The lung immune prognostic index (LIPI) includes pretreatment derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) levels and demonstrated an affordable prognostic value in advanced solid tumors ICI-treated. Methods: We performed a retrospective study including 498 patients affected by advanced solid malignancies treated with ICI or in combination with other agents. We explored prognostic factors associated with early mortality (≤ 90 days). Then, we tested the LIPI score to predict early mortality risk through Cox-regression models and ROC curve analysis. Results: Most patients included were males (63.2%) with ECOG PS 0-1 (85.9%). Non-small cell lung cancer was the most frequent malignancy (80.3%), followed by head-neck (10.7%), genitourinary (5%), and gastrointestinal (4%) tumors. 324 (68.1%) patients received ICI single agent, while 152 (31.9%) ICI plus other agents (chemotherapy, tyrosine kinase inhibitors), primarily as upfront treatment (60.5%). The LIPI score was assessable for 305 patients. The median overall survival was 8.9 months (95%CI, 7.6-11.6), while the median progression-free survival was 4.5 months (95% 3.8-5.6). In a multivariable model, ECOG PS 2 (HR 1.85, p = 0.013) and intermediate-high LIPI score (HR 2.50, p < 0.001) were associated with increased death risk after adjusting for sex, age, histology, metastatic sites, and line of treatment. In the same model, intermediate-high LIPI score (HR 2.45, p < 0.001) and baseline liver metastasis (HR 1.87, p= 0.006) were associated with an increased risk of disease progression.118 patients (24.8%) experienced early mortality. ECOG PS 2 (HR 3.13, p<0.001 ), >3 metastatic sites (HR 1.93, p 0.018), baseline lung (HR 1.62, p 0.014) and liver (HR 1.74, p=0.01) metastases were associated to increased risk of 90-day death at univariate analysis. An intermediate-high LIPI score was associated with increased death risk in the univariate (HR 6.79, 95% CI, 3.24-14.22, p<0.001) and multivariate (HR 6.84, 95% CI, 2.63-17.80, p<0.001) assessments for 90-day mortality. ICI in combination with other agents was associated with reduced 90-day mortality risk also in the multivariable model (HR 0.46, 95% CI, 0.23-0.93, p=0.029). The Area Under the Curve for the LIPI score was 0.743 (95% CI, 0.68-0.80) for 90-day mortality prediction. Conclusions: We evidenced a considerable risk of early mortality under ICI-based strategies. The LIPI score predicted 90-day mortality risk regardless of the treatment and histotype.

Transitions of care with a community-based palliative care program: Results from a pilot project for advanced solid tumor oncology patients.

e24113 Background: Hospice underutilization among patients with advanced cancer at the end of life can result in patients not receiving the full benefit of hospice and lead to significant distress to patients, families, staff and caregivers. Through multidisciplinary root cause analyses, we identified a gap in services where hospice care, if pursued at all, did not occur until late in the course. A pilot program for community-based palliative services partnering with Calvary Hospital Advanced Healthcare Coordination was introduced for patients with advanced solid tumor cancer in February 2022. Methods: Solid tumor oncologists, social workers and palliative care physicians identified eligible patients with advanced stage cancer who may or may not be undergoing cancer-directed treatment with palliative intent. Patients received home-based support by palliative trained nurse practitioners, licensed social workers and spiritual counsel including symptom management, advanced care planning, care coordination and hospice transition if indicated. The pilot was launched initially in thoracic oncology in February 2022, with expansion to all solid tumor oncology patients in April 2022. Results: From February 1, 2022 to December 31, 2022, a total of 34 patients were referred for community-based palliative care services. Only 15/34 (44%) referrals were taken under care. Of the patients taken under care 7/15 (46.7%) were eventually transitioned to hospice services, and 4/15 (26.7%) patients expired while receiving community-based palliative care services. Of the remaining patients that were not taken under care (n = 19), 6/19 (31.5%) required a higher level of care and were hospitalized, 4/19 (21.1%) went directly to hospice care. Process measures including pain scores, completion of advanced care planning documents, depression scores, treatments given while in pilot, number of hospitalizations, as well as patient-reported outcomes are ongoing. Conclusions: Our pilot demonstrates that while community-based palliative care services can potentially bridge patients from palliative care services to hospice at the end of life, several patients may still have been referred “too late” in their course. Future plan-do-study-act cycles aim to continue to improve the number and timing of referrals to this pilot program and evaluate its impact in hospice utilization for patients with advanced cancer at end of life.

Opioid use, gabapentinoid use, and pain-related emergency department visits for patients living with advanced cancer.

12119 Background: Regulatory efforts in response to the United States opioid epidemic have resulted in a decrease in opioid prescribing among oncologists and non-oncologists. Understanding how decreased opioid prescribing affects cancer-related pain can provide key insights into the downstream effects of these efforts. In this study, we explored temporal trends in opioid use, gabapentinoid use, and pain-related emergency department (ED) visits in older adult patients with advanced cancer and those without cancer. Methods: We queried the Surveillance, Epidemiology, and End Results (SEER)-Medicare database from 1/1/2012 to 12/31/2017 to identify patients aged 66 years or older diagnosed with advanced solid tumor cancer (defined as stage IV and/or metastatic disease). A cohort of patients without a cancer diagnosis was identified using the Medicare 5% random sample. The three dependent outcomes assessed were opioid use, gabapentinoid use, and pain-related ED visits. Multivariable logistic regression was used to identify predictors of these outcomes and to calculate the predicted probability of each outcome for patients with and without cancer. We determined the absolute change in the predicted probability of each outcome from 2012 to 2017. Results: A total of 294,113 patients were included in the cohort; 45,899 (15.6%) with cancer and 248,214 (84.4%) without cancer. Between 2012 and 2017, the absolute change in predicted probability of opioid use declined less in the cancer [-6.1%; 68.6% to 62.5%] compared to the non-cancer cohort [-8.2%; 35.8% to 27.6%] (p<.001 for difference). Gabapentinoid use increased more in the cancer [3.9%; 10.8% to 14.7%] than non-cancer [1.8%; 10.5% to 12.3%] cohort (p<.001 for difference). There was no statistically significant change in pain-related ED visits in patients with cancer [0.6%; 12.4% to 13.0%] and a decrease in patients without cancer [-0.5%; 2.6% to 2.1%] (p=0.005 for difference). Conclusions: Our findings showed that opioid use decreased to a lesser degree among older patients with advanced cancer compared to patients without cancer, whereas gabapentinoid use increased to a greater degree among patients with cancer. There was no corresponding rise in pain-related ED visits, suggesting that these shifts in medication use may not have adversely affected this important outcome. [Table: see text]

Phase I first-in-human trial of ABT-301, an oral pan-HDAC inhibitor, in patients with advanced solid tumors.

e15137 Background: ABT-301 (previously known as MPT0E028) is a novel, oral pan-histone deacetylases (HDAC) inhibitor with potent inhibitory activity for HDAC 1, 2, 3 (class I), HDAC 6, 10 (class IIb), modest activity for HDAC 8 (class I) and HDAC 11 (class IV), but no activity for HDAC 4, 5, 7, 9 (class IIa). Preclinical studies showed that ABT-301 had a stronger apoptotic activity and inhibited HDAC activity more potently than vorinostat. ABT-301 exerts antitumor activity as a monotherapy in human colorectal cancer and B-cell lymphoma xenografts and synergistic antitumor activity with immune checkpoint inhibitor in CT26 syngeneic tumor model. Methods: This was a 3+3 Phase 1 dose escalation study to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetic (PK) /pharmacodynamic (PD) profiles for the ABT-301 in patients with locally advanced or metastatic solid cancers. 5 cohorts of 3 or 6 patients received ABT-301 once daily at gradually escalating doses starting from 50 mg. Results: 23 subjects (6 sarcomas and 17 carcinomas) were treated at 5 dose levels (3 at 50, 100, and 250 mg respectively, 6 at 150 mg, and 8 at 200 mg). Cycle 1 DLTs occurred in 5 subjects: 1 at 50 mg (G3 mucositis); 2 at 200 mg (G3 abdominal pain and G4 thrombocytopenia); 2 at 250 mg (G3 vomiting and G4 thrombocytopenia). The MTD was 150 mg. The most common treatment-related adverse events were thrombocytopenia (44%), anemia (18%), nausea (61%), vomiting (44%), anorexia (22%), hyperglycemia (22%), fatigue (18%), and mucositis (18%), which were generally G1 to G2 in severity. No cardiac abnormalities were observed. 1 had a partial response (PR), and 8 achieved SD, resulting in a disease control rate (DCR) of 39%. The PR (a patient with eccrine ductal carcinoma) lasted 24 weeks whereas 5/8 SD patients achieved a sustained condition of 16 to 53 weeks (hepatocellular carcinoma, 53 w; thymic cancer, 49 w; salivary gland carcinoma, 27 w; endometrial stromal carcinoma, 25 w; renal cell carcinoma, 16 w). DCR for 9 patients at MTD was 78% (7/9; 1 PR and 6 SD). Plasma PK showed a dose-dependent increase in ABT-301 exposure. Cmax is 5.5 µM and AUC0-inf is 11.5 µM*h at 150 mg. Increased acetylated histone 3 was observed across all cohorts. Conclusions: ABT-301 was well-tolerated at a daily dose of up to 150 mg and demonstrated objective responses and long-term SD across multiple tumor types at MTD. The safety profile of ABT-301 was superior to known HDAC inhibitors with only predictable HDAC inhibitor-related toxicities observed but no cardiac toxicity, neutropenia, nor lymphopenia elicited. Non-clinical and clinical results suggested the potential clinical development of ABT-301 in combination with myelosuppressive agents and immunotherapies. Phase 2 studies combining PD-1/PD-L1 blockade are being designed. Clinical trial information: NCT02350868 .

Efficacy-effectiveness gap with immune checkpoint inhibitors in solid cancers: A population based cohort study.

6625 Background: Immune checkpoint inhibitors (ICIs) have been central in oncology drug development in the last decade often demonstrating large improvements in overall survival (OS) in pivotal randomized controlled trials (RCTs). Patient selection and/or care may be less stringent in the real world but ascertaining that benefits are translated satisfactorily from pivotal RCTs into the real world is crucial, as patients often base their treatment decisions on outcomes quoted to them from pivotal RCTs. Methods: After necessary ethics approvals, we collected relevant data on all consecutive patients with advanced solid cancers treated with ICIs in the province of Manitoba, Canada from inception to June 30, 2022 using pharmacy database and cancer registry. Eight most frequent ICI indications are included here. Survival probabilities were plotted using Kaplan-Meier Method, and descriptive statistics used to report relationship between variables. To put outcomes into perspective, we report real world data alongside that of pivotal RCTs used to support approvals of respective ICIs by Health Canada and the US FDA. Results: Eight ICI indications included 992 patients followed for a median of 40 months (range: 21-86 months). Patients required to meet precise provincial formulary criteria to receive ICIs, adopted mostly from the inclusion criteria of the corresponding pivotal RCTs. Median OS was shorter in the real world population not only compared to the experimental arms of the respective pivotal RCTs [by a median of 16 months (range: 3 - 38 months)] but also compared to their control arms [by a median of 3 months (range 3 to 32 months)]. This translated into an average of 51.1% (standard deviation: 20.1) compromise in median OS with ICIs in the real world compared to that observed in respective pivotal RCTs. Conclusions: Treatment with ICIs within high standards of practice in a Canadian province overall offered less than half the median OS observed in pivotal RCTs supporting their approvals. Current ICI treatment decisions by patients (and physicians) may therefore be based on highly inaccurate expectations. Our results should inspire rigorous phase IV clinical studies to identify pertinent real-world variables affecting outcomes including treatment related morbidity and mortality, with an ultimate aim to narrow the alarming efficacy-effectiveness gap. [Table: see text]

P-170 The MATTERS trial: A first-in-human study of whole-body hyperthermia in advanced solid cancer patients

P-170 The MATTERS trial: A first-in-human study of whole-body hyperthermia in advanced solid cancer patients

Immune checkpoint inhibition in advanced colorectal cancer with inherited and acquired microsatellite instability: Current state and future directions.

This paper reviews comprehensively the most relevant data on single-agent and combination therapies for advanced colorectal cancer with inherited and acquired microsatellite instability (MSI). We performed a systematic search on PubMed and MEDLINE articles published from inception to December 2022. We have also searched independent websites including U.S. Food and Drug Administration and ClinicalTrials.gov. Performing microsatellite stability testing, tumor mutational burden (TMB), and germline mutation analysis could identify patients with metastatic colorectal cancer that benefit from immune checkpoint inhibitor (ICI) therapy. Single-agent pembrolizumab has proven superiority over traditional chemotherapy in these patients. The nivolumab-ipilimumab is the only combination ICI therapy approved in this space. Recently, the anti-PD-1 antibody dostarlimab was granted Food and Drug Administration approval in refractory tissue-agnostic advanced solid cancers with deficient mismatch repair (dMMR). ICIs are also being studied in the adjuvant/neoadjuvant setting in colon cancer patients with dMMR. Newer agents are being scrutinized in this space as well. More solid data on biomarkers predicting responses in patients with MSI-high or TMB-H to various therapies are needed. Given its both clinical and financial toxicity, it is imperative to determine the optimal duration of ICI therapy in individual patients. Overall, the outlook in advanced colorectal cancer patients with MSI appears optimistic as new and efficacious ICI drugs and combinations are being added to the existing therapeutic armamentarium.

Tumor-infiltrating lymphocyte therapy: Clinical aspects and future developments in this breakthrough cancer treatment.

Tumor-infiltrating lymphocyte (TIL) therapy is a promising approach for treating refractory or advanced solid cancers by using autologous TILs harvested from cancer tissues. Despite the heterogeneity of cancer, TIL therapy can potentially produce a positive therapeutic response, including complete remission. After decades of research on lymphocyte functions, culture/expansion methods, therapeutic protocols, and multiple clinical trials, TIL therapy has finally reached a stage where it can be formally approved for clinical use. TIL therapy is expected to hold a unique position among anti-cancer therapeutic options as a standard intervention. To successfully introduce TIL therapy into clinical settings, there is a need to expand therapeutic indications and set up the best protocols for cancer tissue sampling and manufacturing, and related clinical trials. Moreover, studies on next-generation TIL therapy have already begun, and post-approval real-world data will promote and support further research.

Indoleamine 2,3-dioxygenase 1 in circumventing checkpoint inhibitor responses: Updated.

Metabolic alterations occur commonly in tumor cells as a way to adapt available energetic sources for their proliferation, survival and resistance. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular enzyme catalyzing tryptophan degradation into kynurenine. IDO1 expression shows a rise in the stroma of many types of human cancers, and it provides a negative feedback mechanism for cancer evasion from immunosurveillance. Upregulation of IDO1 correlates with cancer aggression, poor prognosis and shortened patient survival. The increased activity of this endogenous checkpoint impairs effector T cell function, increases regulatory T cell (Treg) population and induces immune tolerance, so its inhibition potentiates anti-tumor immune responses and reshapes immunogenic state of tumor microenvironment (TME) presumably through normalizing effector T cell activity. A point is that the expression of this immunoregulatory marker is upregulated after immune checkpoint inhibitor (ICI) therapy, and that it has inducible effect on expression of other checkpoints. These are indicative of the importance of IDO1 as an attractive immunotherapeutic target and rationalizing combination of IDO1 inhibitors with ICI drugs in patients with advanced solid cancers. In this review, we aimed to discuss about the impact of IDO1 on tumor immune ecosystem, and the IDO1-mediated bypass of ICI therapy. The efficacy of IDO1 inhibitor therapy in combination with ICIs in advanced/metastatic solid tumors is also a focus of this paper.

The impact of the multi-disciplinary molecular tumour board and integrative next generation sequencing on clinical outcomes in advanced solid tumours

The integration of next-generation sequencing (NGS) comprehensive gene profiling (CGP) into clinical practice is playing an increasingly important role in oncology. Therefore, the HKU-HKSH Multi-disciplinary Molecular Tumour Board (MTB) was established to advance precision oncology in Hong Kong. A multicenter retrospective study investigated the feasibility of the HKU-HKSH MTB in determining genome-guided therapy for treatment-refractory solid cancers in Hong Kong. Patients who were presented at the HKU-HKSH MTB between August 2018 and June 2022 were included in this study. The primary study endpoints were the proportion of patients who receive MTB-guided therapy based on genomic analysis and overall survival (OS). Secondary endpoints included the proportion of patients with actionable genomic alterations, objective response rate (ORR), and disease control rate (DCR). The Kaplan-Meier method was used in the survival analyses, and hazard ratios were calculated using univariate Cox regression. 122 patients were reviewed at the HKU-HKSH MTB, and 63% (n=77) adopted treatment per the MTB recommendations. These patients achieved a significantly longer median OS than those who did not receive MTB-guided therapy (12.7 months vs. 5.2 months, P=0.0073). Their ORR and DCR were 29% and 65%, respectively. Our study demonstrated that among patients with heavily pre-treated advanced solid cancers, MTB-guided treatment could positively impact survival outcomes, thus illustrating the applicability of NGS CGPs in real-world clinical practice. The study was supported by the Li Shu Pui Medical Foundation. Dr Aya El Helali was supported by the Li Shu Pui Medical Foundation Fellowship grant from the Li Shu Pui Medical Foundation. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

Capacity of ChatGPT to Identify Guideline-Based Treatments for Advanced Solid Tumors.

ChatGPT, created by OpenAI, is a large language model which has become the fastest growing consumer application in history, recognized for its expansive knowledge of varied subjects. The field of oncology is highly specialized and requires nuanced understanding of medications and conditions. Herein, we sought to better qualify the ability of ChatGPT to name applicable treatments for patients with advanced solid cancers. This observational study was conducted utilizing ChatGPT. The capacity of ChatGPT to tabulate appropriate systemic therapies for new diagnoses of advanced solid malignancies was ascertained through standardized prompts. A ratio of those medications listed by ChatGPT to those suggested in the National Comprehensive Cancer Network (NCCN) guidelines was produced and called the valid therapy quotient (VTQ). Additional descriptive analyses of the VTQ and its association with incidence and type of treatment were performed. Some 51 distinct diagnoses were utilized within this experiment. ChatGPT was able to identify 91 distinct medications in response to prompts related to advanced solid tumors. The overall VTQ is 0.77. In all cases, ChatGPT was able to provide at least one example of systemic therapy suggested by the NCCN. There was a weak association between incidence of each malignancy and the VTQ. The capacity of ChatGPT to identify medications used to treat advanced solid tumors indicates a level of concordance with the NCCN guidelines. As it stands, the role of ChatGPT to assist oncologists and patients in treatment decision making remains unknown. Nonetheless, in future iterations, it may be anticipated that accuracy and consistency in this domain will improve, and further studies will be needed to better quantify its capabilities.

Budget impact analysis of comprehensive genomic profiling for untreated advanced or recurrent solid cancers in Japan

AimsIn Japan, the use of comprehensive genomic profiling (CGP) is only available for cancer patients who have no standard of care (SoC), or those who have completed SoC. This may lead to missed treatment opportunities for patients with druggable alterations. In this study, we evaluated the potential impact of CGP testing before SoC on medical costs and clinical outcome in untreated patients with advanced or recurrent biliary tract cancer (BTC), non-squamous non-small cell lung cancer (NSQ-NSCLC), or colorectal cancer (CRC) in Japan between 2022 and 2026.Materials and methodsWe constructed a decision-tree model reflecting the healthcare environment of Japan, to estimate the clinical outcome and medical costs impact of CGP testing by comparing two groups (with vs without CGP testing before SoC). The epidemiological parameters, detection rates of druggable alterations, and overall survival were collected from literature and claims databases in Japan. Treatment options selected based on druggable alterations were set in the model based on clinical experts’ opinions.ResultsIn 2026, the number of untreated patients with advanced or recurrent BTC, NSQ-NSCLC, and CRC was estimated to be 8600, 32,103, and 24,896, respectively. Compared with the group without CGP testing before SoC, CGP testing before SoC increased druggable alteration detection and treatment rate with matched therapies in all three cancer types. The medical costs per patient per month were estimated to increase with CGP testing before SoC in the three cancer types by 19,600, 2900, and 2200 JPY (145, 21, and 16 USD), respectively.LimitationsOnly those druggable alterations with matched therapies were considered in the analysis model, while the potential impact of other genomic alterations provided by CGP testing was not considered.ConclusionsThe present study suggested that CGP testing before SoC may improve patient outcomes in various cancer types with a limited and controllable increase in medical costs.

Abstract CT182: OXC-101 shows favorable safety profile in first in human phase 1 trial in patients with advanced solid cancer

Abstract Purpose: Many cancers suffer from dysfunctional redox status. MTH1 protects cancer cells from oxidative DNA damage by preventing incorporation of oxidized nucleotides. OXC-101 (Karonudib) is a dual-action mitotic disruptor and MTH1 inhibitor, preventing exit from mitosis and sanitation of oxidative damage to DNA subunits in cancer cells. MASTIFF, (MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class), is a first- in- human phase 1 study, with the primary aim to assess safety, tolerability, and pharmacokinetics (PK) of OXC-101 in patients (pts) with advanced solid malignant tumors (NCT03036228). Methods: Phase 1a study with 3+3 design and intra-patient dose escalation. New cohorts were opened following review of safety and PK data by the safety data monitoring board after the first treatment cycle of 4 weeks (w). All patients had progressive stage IV disease with no treatment options in SOC at inclusion. Radiological tumor response evaluation (RECIST 1.1) was performed 8w of the first 24w, 12w thereafter. The first 29 patients (cohort 1-10) obtained an oral solution. From cohort 11 pts obtained 100mg tablets. Results: 50 subjects (50% female, 50% male) were enrolled at 16 dose levels of OXC-101 at varying posology: 25-900 mg BID, 800-1000mg QD; every second day, once or twice weekly. Mean age was 52 years (range:20-74). 92% of pts had received previous chemotherapy (mean: 5 lines, range:0-34), 18% endocrine therapy and 52% other therapies (incl immunotherapy). OXC-101 was generally well tolerated and with manageable toxicity for dose levels for an average of 121 days (range:2-513 days), and 43/50 subjects discontinued due to disease progression. A total of 20 SAEs were reported: 8 SAEs in 7 subjects were considered related/possibly related to OXC-101 and included pneumonia (3/8), febrile neutropenia (2/8), ileus (1/8), unspecified infection (1/8) and fever (1/8). There were 14 dose-limiting toxicities (DLTs) reported in 7 subjects. At 510mg every second day (1785mg weekly) 2/5 subjects reported G4 neutropenia; at 500mg BID/1000mg QD, twice per week (2000 mg weekly) 2/9 subjects reported G4 neutropenia; at 900mg BID, once weekly (1800 mg weekly) 3/3 subjects reported decrease in white blood count incl. neutropenia. PK was robust and predictable with good exposure correlation between solution and tablet formulation, with an average half-life of 10 hrs in plasma. 15/49 (31%) of the subjects showed stable disease at first radiological evaluation. One subject had stable disease during 73 weeks on OXC-101 treatment. IHC and western blot analysis on tumor biopsies confirmed mechanism of action. A dose of 900mg (500mg mane, 400mg nocte) twice a week (total weekly dose 1800mg) was determined as the Recommended Phase 2 Dose (RP2D). This will be further explored in tumor specific cohorts. Conclusion: OXC-101 has a favorable safety profile with an RP2D of 900mg twice a week. Citation Format: Jeffrey Yachnin, Lars Ny, Teresa Sandvall, Kumar Sanjiv, Martin Scobie, Björn Platzack, Pawel Barancewski, Olof Breuer, Vassilis Gorgoulis, Ioannis S. Pateras, Maria Klockare, Austin Smith, Ulrika Warpman Berglund, Thomas Helleday. OXC-101 shows favorable safety profile in first in human phase 1 trial in patients with advanced solid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT182.

Abstract CT274: Individualized APC targeting VB10.NEO cancer vaccines induce broad neoepitope-specific CD8 T cell responses in patients with advanced or metastatic solid tumors: interim results from a phase 1/2a trial

Abstract Background: VB N-01 is an open label phase 1/2a basket trial to evaluate safety, feasibility, and immunogenicity of a therapeutic DNA cancer vaccine VB10.NEO in patients with locally advanced or metastatic solid cancers. Each VB10.NEO vaccine contains up to 20 neoepitopes selected by the proprietary AI platform NeoSELECT and is designed to target antigen presenting cells using Nykode’ s modular vaccine platform known as Vaccibody™. Patients and Methods: The trial enrolled patients with locally advanced or metastatic solid cancers (renal cell carcinoma, urothelial cancer, non-small cell lung cancer, squamous cell carcinoma of the head and neck, and melanoma), who did not obtain complete responses on immune checkpoint inhibitor therapy (CPI). Up to 14 VB10.NEO doses (3 mg per dose) were administered i.m. by PharmaJet Stratis® for up to 1 year in combination with standard of care (CPI and/or other anti-cancer therapies). Blood samples and tumor biopsies were collected at baseline and during treatment for evaluation of immune responses. Results: At cut-off of May 2022, 41 patients had received at least one vaccination with VB10.NEO. The vaccine was safe and well-tolerated with no new or additional toxicity reported beyond that expected for CPIs alone. All patients displayed immune responses to a minimum of 3 neoepitopes (average 53% of vaccine neoepitopes), assessed by in vitro stimulation (IVS) interferon-gamma ELISpot. T cell responses were elicited in both high and low tumor mutational burden patients (TMB range 2-69mut/Mb). Multiple vaccinations increased the breadth and magnitude of the immune responses with vaccine-induced T cell responses (de novo and/or amplified pre-existing) measured in 95% of eligible patients. IVS intracellular cytokine staining of selected patients demonstrated that the majority of neoepitopes induced polyfunctional CD8 T cells. TCR sequencing of baseline and on-treatment samples (6 patients) showed expansion of T cell clones in both blood and tumor with selected clones being expanded in both compartments. Conclusions: VB10.NEO was generally well tolerated in patients with various pre-treated and advanced cancers. Assessment of neoepitope-specific T cell reactivity demonstrated VB10.NEO-induced broad and long-lasting T cell responses, and the majority of tested neoepitopes activated polyfunctional CD8 T cells. Pre- and post-vaccination TCRseq analysis of blood and tumor samples demonstrated the presence of blood-expanded clones in the on-treatment tumor sample potentially indicating trafficking of VB10.NEO-expanded T cells to the tumor site. Citation Format: Jürgen Krauss, Angela Krakhardt, Stephan Eisenmann, Sebastian Ochsenreither, Kaja C.G Berg, Kushi Kushekhar, Lars-Egil Fallang, Mikkel W. Pedersen, Siri Torhaug, Karsten B. Slot, Karoline Schjetne. Individualized APC targeting VB10.NEO cancer vaccines induce broad neoepitope-specific CD8 T cell responses in patients with advanced or metastatic solid tumors: interim results from a phase 1/2a trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT274.

Abstract 5080: TU2218, a novel ALK5/VEGFR2 dual inhibitor, overcomes tumor endothelial cell anergy and enhances anti-PD1 immunotherapy efficacy

Abstract Immune tolerance by TGF-β and VEGF is inextricably related with poor outcomes of approved anti-PD-(L)1 therapy. Accordingly, a dual target for ALK5 and VEGFR2 via single or combination treatments can be an unequivocal tactic to tune tumor-microenvironment (TME) favorable to ICI, and to essentially overcome immune evasion against TGF-β- and VEGF-enriched tumors. Specifically, several reports from clinical data suggest that VEGF-induced endothelial cell anergy (ECA) acts as a vascular immune checkpoint in TME immune response, and the activation of ECA is associated with worse outcomes. Herein, we demonstrate that TU2218, a first-in-class, orally available inhibitor against ALK5 and VEGFR2 can recover the downregulated endothelial adhesion molecules, i.e., ICAM-1 and VCAM-1, and suppress ECA. In this work, TU2218 completely recovered the expression of ICAM-1 and VCAM-1 on VEGF-induced ECA in HUVECs. The restored level of ICAM-1 and VCAM-1 at 1 μM TU2218 was equivalent to the activity of combined treatment of 1 μM Vactosertib (ALK5 inhibitor) and 25 μg/ml Ramucirumab (VEGFR2 inhibitor). 1 μM of Vactosertib alone, however, did not show such restoration. These results indicate that VEGF-induced ECA is mediated by both VEGFR2 and TGF-β signal, thereby validating the superiority of dual target strategy for ALK5 and VEGFR2 over a single target in overcoming ECA. We further tested if TU2218 could restore VEGF-induced decrease of Jurkat adhesion to HUVECs, considering the close relationship between the expression of adhesion-molecules of endothelial cell surface and the adhesion of lymphocytes to endothelium. TU2218 recovered the number of Jurkat adhering to VEGF-elicited HUVEC monolayer in a dose-dependent manner, but Vactosertib did not. Furthermore, the activity of TU2218 on Jurkat adhesion was reversed by VCAM-1 neutralizing antibody. Therefore, our results demonstrate that TU2218 improves Jurkat adhesion by restoring VCAM-1 expression. Finally, the in vivo translatability of TU2218 in overcoming ECA was confirmed with B16F10-bearing mice, a well-defined immune desert model, after treatments of anti-PD1 antibody, TU2218, or combined regimen for 15 days. TU2218 combined with an anti-PD1 antibody significantly suppressed tumor growth by c.a. 74 % compared to vehicle, thus being superior to a single treatment (e.g., tumor growth inhibition (TGI) 44% for TU2218, TGI 45% for anti-PD1). In this combination, TU2218 increased the number of both CD31+VCAM-1+ and IFNγ+CD8+ T cells in the tumor. We conclude that TU2218 leads not only to the enhancement of T cell-traffic toward TME, but also to the conversion of immune balance favorable to anti-PD1 therapy. The Phase 1b trial of TU2218 combined with pembrolizumab is underway for advanced solid cancers (NCT05204862). Citation Format: Jihyun Lee, Nam-hoon Kim, Hun-Taek Kim. TU2218, a novel ALK5/VEGFR2 dual inhibitor, overcomes tumor endothelial cell anergy and enhances anti-PD1 immunotherapy efficacy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5080.

Quality of life and psychological distress of patients with advanced cancer in the Philippines.

This study aimed to describe the quality of life (QOL) and psychological distress (anxiety and depression) of Filipino patients with advanced solid cancers and identify sociodemographic and clinical-related factors associated with them. 195 patients with advanced cancer were recruited from a major hospital treating cancer patients in the Philippines. Participants completed self-reported surveys on Quality-of-life (QOL-FACT-G) and psychological distress (HADS-D, HADS-A). Multi-variable OLS regression models were performed where sociodemographic, health history and clinical characteristics were included as predictors. The average total FACT-G score was 65.39/108 (Standard deviation (SD) = 13.76), with the physical well-being scale having the lowest scores (M = 14.14/28, SD = 5.92). The two most common symptoms reported were fatigue (88%) and pain (86.5%). Physical symptom burden was significantly negatively associated with QOL and psychological distress. The average HADS-total score was 14.46/21 (SD = 5.77), with 8% with probable anxiety and 27% with probable depression. Participants who reported greater reliance on their spiritual faith for strength in coping with illness reported lower depression scores. Our findings underline the importance of understanding the multi-dimensional outcomes of Filipino advanced cancer patients. Results may be used to improve QOL and reduce the psychological distress of advanced cancer patients.

A prospective study of psychological distress among patients with advanced cancer and their caregivers.

Cancer can impact the psychological well-being of both patients and their informal caregivers. We investigated the joint trajectories of psychological distress among Singaporean advanced cancer patients-caregiver dyads. We also examined predictors of trajectory group membership. This study utilised data from 299 patients with advanced solid cancer and their caregivers over 33 months (12 times points). Group-based trajectory modelling was used to examine the joint trajectories of patient anxiety, patient depression, caregiver anxiety and caregiver depression scores using the Hospital Anxiety and Depression Scale. Four joint trajectory groups were found: (1) Patient-caregiver low distress (27%), (2) patient-caregiver increasing distress (28.5%), (3) patient low- caregiver borderline distress (25%), (4) patient-caregiver high distress (19.5%). Dyads where the patient is below 50 years of age were more likely to be in Group 4. Dyads where caregiver-patient emotional closeness was low were more likely to be in Groups 2 or 4 where dyads reported increasing/high distress. Dyads that reported financial inadequacy were more likely to be in Groups 2, 3 and 4, while dyads with caregivers who were employed were more likely to be in group 3. A substantial proportion of patients and caregivers reported anxiety and/or depression that lasted or increased throughout the study duration. We found significant heterogeneity in how dyads experienced psychological distress, suggesting that efforts should consider dyadic differences when providing psychological support. Particular focus should be placed on identifying dyads that are at risk and who require additional support.

ELK3-CXCL16 axis determines natural killer cell cytotoxicity via the chemotactic activity of CXCL16 in triple negative breast cancer

ABSTRACT Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer because of its aggressive behavior and the limited therapeutic strategies available. In the last decade, immunotherapy has become a promising treatment to prolong survival in advanced solid cancers including TNBC. However, the efficacy of immunotherapy in solid cancers remains limited because solid tumors contain few tumor-infiltrating lymphocytes. Here, we show that targeting an ETS transcription factor ELK3 (ELK3) recruits immune cells including natural killer (NK) cells into tumors via the chemotactic activity of chemokine. ELK3 depletion increases CXCL16 expression level and promotes NK cell cytotoxicity through CXCL16-mediated NK cell recruitment in TNBC. In silico analysis showed that ELK3 is negatively correlated with CXCL16 expression in breast cancer patient samples. Low expression of ELK3 and high expression of CXCL16 were associated with a better prognosis. Low expression of ELK3 and high expression of CXCL16 were associated with increased expression of NK cell-related genes. Our findings demonstrate that the ELK3-CXCL16 axis modulates NK cell recruitment to increase NK cell cytotoxicity, suggesting that targeting the ELK3 gene could be an adjuvant strategy for increasing the efficacy of immunotherapy in TNBC.