Refractory Tumors Research Articles

Effects of Aureobasidium Pullulans produced β-1,3-1,6-glucan on CA19-9, sCD44, IgA and sCD209 in patients undergoing surgical resection of malignant pancreatic tumors.

96 Background: Pancreatic cancer is a highly refractory tumor with poor prognosis, which aggressively progresses by suppressing the immunity. Surgical procedure related stress further weakens the immunity and aids cancer stem cell metastases, warranting immune enhancement strategies. AFO-202 strain of Aureobasidium Pullulans produced β-1,3-1,6 glucan (Nichi BRITE), having yielded immune enhancement in earlier studies, we evaluated its effects in patients undergoing surgical resection of malignant pancreatic tumors. Methods: 30 subjects in two groups were enrolled; control arm (n=15, "P" group) received a placebo, and treatment arm (n=15, "G" group) received Nichi BRITE 250mg/day, in three divided doses, for 22 days from the pre-operative day. Serum beta glucan specific IgA2 (BG-IgA), total IgA (IgA), sCD209, Serum Amyloid A (SAA), sCD44 and CA19-9 were evaluated at base line and at periodic intervals. Results: sCD44 significantly decreased 48.94% in “G” group and only 4.58% in “P” group (p = < 0.0001) on day 21. sCD209 on day 21 in “G” group increased by 54.68% (p = 0.04) against 15.03% in “P”. BG-IgA at day 10 increased around 150% in “G”, and only by 6% in “P”. Total IgA, increased by 20.60% in “G” and only 5.73% in “P”. SAA increased to 251.32% in “G” on day 21 and in “P” it decreased by 6.11%. Decreased sCD44 when correlated against Neutrophil to Lymphocyte Ratio (NLR), a significant positive correlation was in “G” (r statistic= 0.758; p-value =0.006; 95% CI= 0.2907~0.9335), but a negative correlation in “P”. Pancreatic cancer marker CA19-9 decreased significantly in three months follow up in “G” (-86.02 U/ml) whereas it increased in “P” by +5.91 U/ml. Mean survival of Nichi BRITE group was 25.9 months against 22.3 months in “P” group. Conclusions: Administration of Nichi BRITE glucans to patients undergoing surgical resection of malignant pancreatic tumor was safe and it enhanced biomarkers of innate and adaptive immunity. Nichi BRITE significantly decreased the circulating cancer stem cell marker sCD44 implying a lesser recurrence risk, especially in patients with high NLR ratio who have a poor prognosis, and significantly reduced the CA 19-9 levels implying a better prognosis, making us recommend it as an adjuvant to patients undergoing surgeries for malignant tumors, and be included in the guidelines of clinical nutrition.

Commercialization of the Xalkori Pediatric Multiparticulate Product Using Quality-by-Design Principles.

A pediatric dosage form for crizotinib (Xalkori) was commercialized using quality-by-design principles in a material-sparing fashion. The dosage form consists of spherical multiparticulates (microspheres or pellets) that are coated and encapsulated in capsules for opening. The crizotinib (Xalkori)-coated pellet product is approved in the US for pediatric patients 1 year of age and older and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) and unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive. The product is also approved in the US for adult patients with non-small cell lung cancer (NSCLC) who are unable to swallow intact capsules. The lipid multiparticulate is composed of a lipid matrix, a dissolution enhancer, and an active pharmaceutical ingredient (API). The API, which remains crystalline, is embedded within the microsphere at a 60% drug loading in the uncoated lipid multiparticulate to enable dose flexibility. The melt spray congealing technique using a rotary atomizer is used to manufacture the lipid multiparticulate. Following melt spray congealing, a barrier coating is applied via fluid bed coating. Due to their particle size and content uniformity, this dosage form provides the dosing flexibility and swallowability needed for the pediatric population. The required pediatric dose is achieved by opening the capsules and combining doses of different encapsulated dose strengths, followed by administration of the multiparticulates directly to the mouth. The encapsulation process was optimized through equipment modifications and by using a design of experiments approach to understand the operating space. A limited number of development batches produced using commercial-scale equipment were leveraged to design, understand, and verify the manufacturing process space. The quality by design and material-sparing approach taken to design the melt spray congeal and encapsulation manufacturing processes resulted in a pediatric product with exceptional content uniformity (a 95% confidence and 99% probability of passing USP <905> content uniformity testing for future batches).

Research Progress on the Influence of Blood Tumor Microen-vironment on the Efficacy and the Adverse Reactions of CAR-T Cell Immunotherapy--Review

The application of chimeric antigen receptor T cell (CAR-T) immunotherapy has ushered in a new era in cancer therapy, especially in the treatment of many kinds of refractory malignant tumors. The curative effect is significant for refractory/recurrent hematologic malignancies, such as acute leukemia, lymphoma, and multiple myeloma (MM). Tumor microenvironment (TME) is closely related to the efficacy and adverse reactions of CAR-T therapy. TME not only affects the activity of CAR-T cells, reduces their anti-tumor ability, but also directly involved in the occurrence and development of CAR-T cell therapy-related adverse reactions, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Therefore, a deeper understanding of the role of blood TME in the process of CAR-T immunotherapy and the occurrence and development of adverse reactions is helpful for the application of CAR-T therapy in hematological malignancies. In this review, the influence of blood TME on the efficacy and adverse reactions of CAR-T immunotherapy was briefly summarized, aiming to provide evidence-based support for the clinical optimization of therapeutic regimen of refractory/recurrent hematologic malignancies.

NDRG1 enhances the sensitivity to Cetuximab by promoting Stat1 ubiquitylation in colorectal cancer

IntroductionCetuximab (CTX) is an effective targeted drug for the treatment of metastatic colorectal cancer, but it is effective only in patients with wild-type KRAS genes. Even in this subset of patients, the sensitivity of CTX in patients with right hemi-colon cancer is much lower than that in patients with left hemi-colon cancer. This significantly limits its clinical application. Therefore, further elucidation of the underlying molecular mechanisms is needed. N-myc downstream-regulated gene 1 (NDRG1) plays an important role in solid tumor invasion and metastasis, but whether it can influence CTX sensitivity has not been thoroughly investigated. ObjectiveOur study aimed to identify a novel mechanism by which NDRG1 affects CTX sensitivity. MethodsThrough mass spectrometry analysis of our previously constructed CTX-resistant RKO and HCT116 cells, we found that the signal transducer and activator of transcription-1 (Stat1) might be a potential target of NDRG1. By knocking out NDRG1 or/and Stat1 genes, we then applied the loss-of-function experiments to explore the regulatory relationship between NDRG1 and Stat1 and their roles in the cell cycle, epithelial-mesenchymal transition (EMT), and the sensitivity to CTX in these two colorectal cancer (CRC) cells. Finally, we used the nude-mouse transplanted tumor model and human CRC samples to verify the expression of NDRG1 and Stat1 and their impact on CTX sensitivity in vivo. ResultsStat1 was upregulated in CTX-resistant cells, whereas NDRG1 was downregulated. Mechanically, NDRG1 was inversely correlated with Stat1 expression. It suppressed CRC cell proliferation, migration, and invasion, and promoted apoptosis and epithelial-mesenchymal transition (EMT) by inhibiting Stat1. In addition, NDRG1 directly interacted with Stat1 and promoted Smurf1-induced Stat1 ubiquitination. Importantly, this novel NDRG1-dependent regulatory loop also enhanced CTX sensitivity both in vitro and in vivo. ConclusionOur study revealed that NDRG1 enhanced the sensitivity to Cetuximab by inhibiting Stat1 expression and promoting its ubiquitination in colorectal cancer, elucidating NDRG1 might be a potential therapeutic target for refractory CTX-resistant CRC tumors. But its clinical value still needs to be validated in a larger sample size as well as a different genetic background.

An ultra-long-acting L-asparaginase synergizes with an immune checkpoint inhibitor in starvation-immunotherapy of metastatic solid tumors

Metastasis stands as the primary contributor to mortality associated with tumors. Chemotherapy and immunotherapy are frequently utilized in the management of metastatic solid tumors. Nevertheless, these therapeutic modalities are linked to serious adverse effects and limited effectiveness in preventing metastasis. Here, we report a novel therapeutic strategy named starvation-immunotherapy, wherein an immune checkpoint inhibitor is combined with an ultra-long-acting L-asparaginase that is a fusion protein comprising L-asparaginase (ASNase) and an elastin-like polypeptide (ELP), termed ASNase-ELP. ASNase-ELP's thermosensitivity enables it to generate an in-situ depot following an intratumoral injection, yielding increased dose tolerance, improved pharmacokinetics, sustained release, optimized biodistribution, and augmented tumor retention compared to free ASNase. As a result, in murine models of oral cancer, melanoma, and cervical cancer, the antitumor efficacy of ASNase-ELP by selectively and sustainably depleting L-asparagine essential for tumor cell survival was substantially superior to that of ASNase or Cisplatin, a first-line anti-solid tumor medicine, without any observable adverse effects. Furthermore, the combination of ASNase-ELP and an immune checkpoint inhibitor was more effective than either therapy alone in impeding melanoma metastasis. Overall, the synergistic strategy of starvation-immunotherapy holds excellent promise in reshaping the therapeutic landscape of refractory metastatic tumors and offering a new alternative for next-generation oncology treatments.

Different efficacy of tyrosine kinase inhibitors by KIT and PGFRA mutations identified in circulating tumor DNA for the treatment of refractory gastrointestinal stromal tumors

BackgroundWhile advanced gastrointestinal stromal tumors (GISTs) are primarily treated with tyrosine kinase inhibitors (TKIs), acquired resistance from specific mutations in KIT or PDGFRA frequently occurs. We aimed to assess the utility of circulating tumor DNA (ctDNA) as a modality of therapeutic decision-making in advanced GIST.MethodsWe conducted a pooled analysis of SCRUM-Japan studies for advanced GIST patients. We compared patient characteristics analyzed with tissue and blood samples, assessed gene alteration profiles, and evaluated prognostic implications from ctDNA status.ResultsIn 133 patients, tissue and blood samples were analyzed for 89 and 44 patients, respectively. ctDNA was detected in 72.7% of cases; no prior treatment or progressive disease was significantly associated with ctDNA-positivity. ctDNA-positive patients had significantly shorter progression-free survival compared with ctDNA-negative patients (hazard ratio = 3.92; P = 0.007). ctDNA genotyping revealed a complex landscape of gene alterations, characterized by multi-exonic mutations in KIT, compared with tissue-based analysis. Patients who received TKIs matched to the identified KIT mutation in ctDNA demonstrated significantly longer PFS than those with unmatched treatment (median, 8.23 vs. 2.43 months; P < 0.001).ConclusionsctDNA-based analysis facilitates assessment of disease status and genomic profiles, thus potentially assisting in identifying optimal therapeutic strategies for advanced GIST patients.

SEOM-GG clinical guidelines for the management of germ-cell testicular cancer (2023)

Testicular germ cell tumors are the most common tumors in adolescent and young men. They are curable malignancies that should be treated with curative intent, minimizing acute and long-term side effects. Inguinal orchiectomy is the main diagnostic procedure, and is also curative for most localized tumors, while patients with unfavorable risk factors for recurrence, or those who are unable or unwilling to undergo close follow-up, may require adjuvant treatment. Patients with persistent markers after orchiectomy or advanced disease at diagnosis should be staged and classified according to the IGCCCG prognostic classification. BEP is the most recommended chemotherapy, but other schedules such as EP or VIP may be used to avoid bleomycin in some patients. Efforts should be made to avoid unnecessary delays and dose reductions wherever possible. Insufficient marker decline after each cycle is associated with poor prognosis. Management of residual masses after chemotherapy differs between patients with seminoma and non-seminoma tumors. Patients at high risk of relapse, those with refractory tumors, or those who relapse after chemotherapy should be managed by multidisciplinary teams in experienced centers. Salvage treatment for these patients includes conventional-dose chemotherapy (TIP) and/or high-dose chemotherapy, although the best regimen and strategy for each subgroup of patients is not yet well established. In late recurrences, early complete surgical resection should be performed when feasible. Given the high cure rate of TGCT, oncologists should work with patients to prevent and identify potential long-term side effects of the treatment. The above recommendations also apply to extragonadal retroperitoneal and mediastinal tumors.

Metronomic chemotherapy in pediatric neurooncology: insight the problem. A review

Metronomic chemotherapy (MCT) is a promising direction of anticancer therapy, as well as in pediatric oncology, and its administration in patients with refractory and recurrent tumors of the central nervous system becomes increasingly relevant. Being a regimen of low doses of antitumor agents with different mechanisms of action in a continuous mode for a long time, it allows to overcome the resistance of tumor cells and to minimize the toxic effects of treatment. Today, the issues of rational choice of MCT regimens, which are dependent on the type of tumor, and the application of biomarkers of its effectiveness, remain controversial. The article discusses in detail the biological effects of MCT with an accent on antiangiogenic one, as well as the possibilities and limitations of MCT application in pediatric practice and the results of studies in tumors of the central nervous system.

Oncolytic Activity of Sindbis Virus with the Help of GM-CSF in Hepatocellular Carcinoma.

Hepatocellular carcinoma is a refractory tumor with poor prognosis and high mortality. Many oncolytic viruses are currently being investigated for the treatment of hepatocellular carcinoma. Based on previous studies, we constructed a recombinant GM-CSF-carrying Sindbis virus, named SINV-GM-CSF, which contains a mutation (G to S) at amino acid 285 in the nsp1 protein of the viral vector. The potential of this mutated vector for liver cancer therapy was verified at the cellular level and in vivo, respectively, and the changes in the tumor microenvironment after treatment were also described. The results showed that the Sindbis virus could effectively infect hepatocellular carcinoma cell lines and induce cell death. Furthermore, the addition of GM-CSF enhanced the tumor-killing effect of the Sindbis virus and increased the number of immune cells in the intra-tumor microenvironment during the treatment. In particular, SINV-GM-CSF was able to efficiently kill tumors in a mouse tumor model of hepatocellular carcinoma by regulating the elevation of M1-type macrophages (which have a tumor-resistant ability) and the decrease in M2-type macrophages (which have a tumor-promoting capacity). Overall, SINV-GM-CSF is an attractive vector platform with clinical potential for use as a safe and effective oncolytic virus.

Pharmacotherapy of autoimmune rheumatic diseases – from monoclonal antibodies to CAR T cells: 20 years later

Autoimmunity is a pathological process associated with a violation of immunological tolerance to normal structural components of the body (autoantigens), associated with the predominance of active (adaptive) immunity and manifested by hyperproduction of autoantibodies. Systemic autoimmune rheumatic diseases (SARDs) are among the most common and severe nosological forms of this pathology associated with autoimmunity. Problems of pharmacotherapy of SARDs are the subject of intensive research. At the beginning of the 21st century, more than 20 biologic agents were developed for the treatment of rheumatoid arthritis – monoclonal antibodies (mAbs) and recombinant proteins that control inflammation associated with the overproduction of “pro-inflammatory” cytokines, the use of which has dramatically improved the results of pharmacotherapy. However, much less research has been devoted to studying the possibilities of pharmacotherapy aimed at selective suppression of the “autoimmune” component of the pathogenesis of SADRs associated with uncontrolled activation of B cells and restoration of immunological tolerance to autoantigens. In the spectrum of drugs whose mechanism of action is associated with the suppression of pathological activation of B cells, the leading place is occupied by rituximab (RTM). It is noteworthy that 20 years ago (2004), a group of researchers led by prof. J.C. Edwards first demonstrated the effectiveness of RTM in patients with RA, which was soon successfully repositioned to treat a wide range of SARDs. A major achievement in the pharmacotherapy of SARDs is associated with the use of CAR (сhimeric antigen receptor) T cell therapy, developed for the treatment of refractory hematological tumors. The main component of CART-cells is a genetically engineered T-cell receptor that recognizes the target antigen without the participation of the major histocompatibility complex. Although limited, extremely impressive data regarding high remission rates have been obtained by adapting CD19 CART-cell therapy to treat patients with severe systemic lupus erythematosus (SLE) and other SARDs refractory to standard immunosuppressive medications. The article discusses the results of the use of CART-cell therapy in SLE and other SARDs and prospects for further research.

Antibody-drug conjugates as a novel therapeutic modality to treat recurrent refractory germ cell tumors.

This review provides a rationale for using the Food and Drug Administration (FDA)-approved antibody-drug conjugates (ADCs) for implementing as therapy in recurrent refractory germ cell tumors similar to their position in the treatment of other types of chemoresistant solid tumors. Germ cell tumors (GCTs) originate from germ cells; they most frequently develop in ovaries or in the testes, while being the most common type of malignancy in young men. GCTs are very sensitive to cisplatin-based chemotherapy, but therapeutic resistance occurs in a considerable number of cases, which is associated with disease recurrence and poor patient prognosis. ADCs are a novel type of targeted antitumor agents that combine tumor antigen-specific monoclonal antibodies with chemically linked chemotherapeutic drugs (payload) exerting a cytotoxic effect. Several FDA-approved ADCs use as targeting moieties the antigens that are also detected in the GCTs, offering a benefit of this type of targeted therapy even for patients with relapsed/refractory testicular GCTs (rrTGCT) unresponsive to standard chemotherapy.

Clinical Application and Prospect of New Radiotherapy Technology in Cancer Treatment

Objective: Carbon ion therapy, a new radiotherapy technology, has shown its remarkable efficacy and potential in cancer treatment, especially in the treatment of refractory tumors. Methods: This paper clarifies the physical basis, technological change, and clinical practice effect of carbon ion therapy, comprehensively discusses the future prospects, and evaluates the clinical application effect. Results: The technology has significantly improved the treatment effectiveness and received a positive response from patients. Conclusion: Carbon ion therapy technology has become a major innovation in the field of cancer treatment. It not only has a profound impact on many current cancer therapy methods but also indicates the application blueprint for a wider range of cancer types in the future, showing a new chapter of medical technology advancement.

TRLS-05. A PILOT STUDY TO ASSESS THE SAFETY, FEASIBILITY, AND PRELIMINARY EFFICACY OF A NEOEPITOPE-BASED PERSONALIZED DNA VACCINE APPROACH IN PEDIATRIC PATIENTS WITH RECURRENT BRAIN TUMORS

Abstract BACKGROUND Pediatric brain tumors present a heterogeneous group of neoplasms with limited treatment options, especially at relapse. Hence, innovative therapeutic strategies are imperative. Immunotherapy, specifically immunogenomics, utilizing personalized vaccines based on tumor-specific neoantigens, has emerged as a promising option in other tumors. However, the feasibility of this approach in pediatric brain tumors remain largely unexplored. METHODS This single institution feasibility study focuses on sequencing analyses of pediatric brain tumors to identify mutant tumor-specific antigens. The study employs tumor/normal exome sequencing and cDNA-capture sequencing to identify and confirm mutant antigens, respectively. An epitope prediction algorithm prioritizes these antigens with subsequent confirmation of binding to HLA class I molecules. The neoantigen DNA vaccine strategy, utilizing a polyepitope DNA vaccine, is designed to target up to 20 prioritized antigens. The TDS-IM v2.0 device facilitates the administration of the vaccine. The primary objective of the study is to determine the feasibility of adjuvant personalized neoantigen DNA vaccine administration in patients with recurrent or refractory pediatric brain tumors. RESULTS We anticipate the identification of actionable neoantigens in pediatric brain tumors to support the potential efficacy of personalized DNA vaccines. The proposed sequencing strategies, epitope prediction algorithm, and in vitrobinding studies aim to establish a comprehensive methodology for neoantigen identification and prioritization. During the meeting, we will present the study background, rationale, detailed methodology, and design to inform the brain tumor community of this study. CONCLUSION This feasibility study is poised to provide essential insights into the development of personalized neoantigen DNA vaccines for recurrent or refractory pediatric brain tumors and aims to demonstrate safety, feasibility, and potential efficacy in targeting mutant tumor-specific antigens. The findings from this study will lay the groundwork for future clinical trials, evaluating the impact of personalized immunotherapy on progression-free and overall survival rates in this challenging patient population.

IMMU-17. A PHASE I STUDY OF INTRATUMORAL/PERITUMORAL HERPES SIMPLEX VIRUS-1 MUTANT HSV1716 IN PATIENTS WITH REFRACTORY OF RECURRENT HIGH-GRADE GLIOMAS: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY

Abstract BACKGROUND Immune-modulatory strategies, including checkpoint inhibition and tumor vaccines, have been tested in efforts to mitigate the pro-tumor microenvironment in pediatric high-grade glioma (pHGG). HSV1716 is a first-generation oncolytic virus that was previously reported safe with evidence of response in pediatric patients with relapsed or refractory extracranial tumors and in adults with high-grade glioma. METHODS PBTC-037 was a multicenter, phase I trial developed and performed by the Pediatric Brain Tumor Consortium (PBTC) to estimate the maximum tolerated dose or recommended phase II dose of HSV1716 administered during surgical resection. Patients aged 12 to 21 years with recurrent or refractory pHGG for whom surgical resection was clinically indicated were eligible. After maximal tumor resection, patients received one intraoperative dose of HSV1716. RESULTS Two patients were enrolled; one was later deemed ineligible (due to out-of-window screening evaluations) yet was continued in follow up for safety. Shortly after enrollment of the 2 patients, the study was closed to accrual due to a change in the sponsor’s investment focus. One patient completed the 8-week reporting period without toxicities. The only grade 3 or higher adverse event noted was grade 3 hyperglycemia at 2- and 3-months post injection. The second patient that was later deemed ineligible received the injection of HSV1716 and had no evidence of dose-limiting toxicity. The two patients had progressive disease 1.9 and 2.9 months after enrollment; both eventually died due to progressive disease at 7.5 months. CONCLUSIONS We describe the administration of HSV1716 to two pediatric patients with recurrent high-grade glioma, without evidence of dose-limiting toxicity. Oncolytic viruses are currently being tested in pediatric patients in larger trials and in combinatorial trials in other tumor types. Despite the limited numbers, the data presented here will hopefully provide incremental steps toward improved immunovirotherapy of pediatric brain tumors.

Tumor microenvironment characteristics of lipid metabolism reprogramming related to ferroptosis and EndMT influencing prognosis in gastric cancer

BackgroundGastric cancer (GC) is a refractory malignant tumor with high tumor heterogeneity, a low rate of early diagnosis, and poor patient prognosis. Lipid metabolism reprogramming plays a critical role in tumorigenesis and progression, but its prognostic role and regulatory mechanism in GC are rarely studied. Thus, the identification of signatures related to lipid metabolism is necessary and may present a new avenue for improving the overall prognosis of GC. MethodsLipid metabolism-associated genes (LMAGs) with differential expression in tumor and tumor-adjacent tissue were acquired to identify lipid metabolism-associated subtypes. The differentially expressed genes (DEGs) between the two clusters were then utilized for prognostic analysis and signature construction. Additionally, pathway enrichment analysis and immune cell infiltration analysis were employed to identify the characteristics of the prognostic model. Further analyses were conducted at the single-cell level to better understand the model’s prognostic mechanism. Finally, the prediction of immunotherapy response was used to suggest potential treatments. ResultsTwo lipid metabolism-associated subtypes were identified and 9 prognosis-related genes from the DEGs between the two clusters were collected for the construction of the prognostic model named lipid metabolism-associated signature (LMAS). Then we found the low LMAS patients with favorable prognoses were more sensitive to ferroptosis in the Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD). Meanwhile, the tumor cells exhibiting high levels of lipid peroxidation and accumulation of reactive oxygen species (ROS) in single-cell levels were primarily enriched in the low LMAS group, which was more likely to induce ferroptosis. In addition, endothelial cells and cancer-associated fibroblasts (CAFs) facilitated tumor angiogenesis, proliferation, invasion, and metastasis through endothelial-mesenchymal transition (EndMT), affecting the prognosis of the patients with high LMAS scores. Moreover, CD1C− CD141− dendritic cells (DCs) also secreted pro-tumorigenic cytokines to regulate the function of endothelial cells and CAFs. Finally, the patients with low LMAS scores might have better efficacy in immunotherapy. ConclusionsA LMAS was constructed to guide GC prognosis and therapy. Meanwhile, a novel anti-tumor effect was found in lipid metabolism reprogramming of GC which improved patients’ prognosis by regulating the sensitivity of tumor cells to ferroptosis. Moreover, EndMT may have a negative impact on GC prognosis.

Feasibility of implementing whole genome sequencing into routine oncology care.

e15181 Background: The promise of precision oncology to deliver improved patient outcomes is dependent on the availability and appropriate interpretation of individual patient tumor sequencing results. While routine use and clinical utility for comprehensive genomic profiling (CGP) is growing, there are limited data in the U.S. to support the use of whole genome sequencing (WGS) outside of limited specific indications (i.e. acute myeloid leukemia, pediatric, sarcoma). This study highlights reports on the feasibility from a pilot project offering paired germline/somatic WGS to a cohort of oncology patients at an academic medical center. Methods: Eligible patients included those with an active cancer diagnosis, available tumor, and a treating provider within Weill Cornell. There were no specific restrictions. Providers selected patients with newly diagnosed metastatic cancers, rare tumors, refractory tumors, and/or those with uninformative germline testing for hereditary cancer. Reportable germline findings were pathogenic or likely pathogenic (P/LP) variants in known cancer predisposition genes and/or genes on the American College of Medical Genetics list of reportable secondary findings. Clinical actionability of somatic results was determined using the cBioPortal Database and Oncology Knowledgebase. Ordering providers disclosed results to patients. Barriers to enrollment were explored and addressed. Results: Between January 2021 and December 2023, 82 patients had germline/somatic WGS. The most common tumors included breast (17%), prostate (11%), renal (10%), lung (7%), bladder (7%), and colon (5%), with 48% of the cohort represented by rare tumors. Six cases (7.3%) had insufficient quantity/quality. WGS detected single nucleotide variants in 84% (n = 69) of cases, with 39% (n = 27) of those having clinical actionability in the patient’s tumor. Additional somatic results included copy number variants in 83% (n = 68) and transcriptome variants in 17% (n = 14). P/LP germline variants were found in 17% (n = 14) of cases. Barriers to enrollment included: difficulty identifying which patients would benefit most from WGS, lengthy in-person consent process, limited access to pretest genetic counseling, and difficulty procuring and processing tissue specimens. Availability of reflexive in-house CGP since August 2022 also resulted in decreased uptake of this service. Several interventions were implemented to address the barriers, resulting in an increase in enrollment. Conclusions: Paired germline/somatic WGS identified clinically relevant variants for patients with diverse tumors. Results were used to direct treatment decisions and determine eligibility for clinical trials as well as inform hereditary cancer predisposition. An assessment period after WGS implementation is needed to improve workflow. Further research aims to determine optimal accessibility and utilization of WGS for oncologic patients.

Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.

The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor. As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m2/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m2/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS). Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF-altered CNS tumors achieved stable disease >6 months. Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m2/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

Prognostic and predictive value of ultrasensitive ctDNA monitoring in a metastatic pan-cancer cohort treated with immune checkpoint inhibitors in the context of phase 1 clinical trials.

2510 Background: Determining which patients will achieve clinical benefit from immune checkpoint inhibition (ICI) therapy remains an open question. Liquid biopsy tests to assess baseline and early dynamics of circulating tumor DNA (ctDNA) may allow clinicians to track response more granularly and predict ICI response or resistance prior to imaging. However, lack of sensitivity may hinder accurate detection of low ctDNA levels in tumors with low shedding rates or during substantial drops and clearance in response. Methods: This study represents a cohort of 175 patients with refractory metastatic tumors from 18 different cancer types, who received 1-3 successive lines of ICI treatment in the context of phase-1 clinical trials. Thus far, 609 plasma samples from 90 stage-IV cancer patients receiving immune checkpoint inhibitor (ICI) treatment have been processed. ctDNA was profiled using the NeXT Personal assay, a liquid biopsy platform that leverages whole-genome sequencing of tumor and normal samples to create custom, patient-specific panels that include up to 1,800 somatic variants. This enables the detection of molecular residual disease (MRD) down to a detection threshold of 1 part per million (PPM) of ctDNA. Results: NeXT Personal assay detected positive levels of ctDNA in 99% (81/82) of plasma baseline samples, with a wide dynamic range, extending from 4.2 PPM (~0.00042% TF) to ~640,000 PPM (~64% TF) (median limit of detection = 2 PPM, 0.0002% TF). Lower ctDNA values at baseline were correlated with increased duration of PFS (log-rank p=0.017, HR=0.57, 95% CI 0.36-0.91) and extended OS (log-rank p=0.002, HR=0.46, 95% CI 0.28-0.75). Early reduction in ctDNA level from baseline to treatment cycle 3 was associated with significant increases in PFS (log-rank p=0.001, HR=0.36, 95% CI 0.19-0.67) and OS (log-rank p=0.015, HR=0.44, 95% CI 0.22-0.87), representing a &gt;3-fold increase in both median PFS and OS. ctDNA clearance resulted in significant improvement in both PFS and OS (PFS: log-rank p=0.002, HR=0.24, 95% CI 0.09-0.62; OS: log-rank p=0.01, HR=0.29, 95% CI 0.1-0.8). All plasma timepoints from periods of durable complete response (CR) assessed via RECIST 1.1 were ctDNA-negative, with a molecular clearance lead time of 277 days over radiographically confirmed CR. Conclusions: We demonstrate that early ctDNA dynamics are predictive of long-term ICI response in the advanced, pan-cancer ECT setting. Even in this refractory advanced cancer cohort, an ultra-sensitive assay was required for accurate MRD status determination, with low ctDNA detections down to 4.2 PPM that might otherwise have been missed. Taken together, these findings suggest a high sensitivity ctDNA assay is crucial for accurate monitoring of ICI response, providing information for more accurate patient management.

Combination targeted therapy of avapritinib and sunitinib for patients with refractory advanced gastrointestinal stromal tumors after failure of standard treatments: Early results from a multi-institutional pilot study.

Combination targeted therapy of avapritinib and sunitinib for patients with refractory advanced gastrointestinal stromal tumors after failure of standard treatments: Early results from a multi-institutional pilot study.

Neoadjuvant nivolumab plus paclitaxel/cisplatin- chemo-radiotherapy (neo-NTP-CRT) followed by esophagectomy for locally advanced esophageal squamous cell carcinoma (ESCC): A phase II study.

e16098 Background: Adjuvant nivolumab has shown efficacy in reducing recurrence in patients (pts) with locoregional esophageal cancer harboring pathologic residual disease following neoadjuvant chemoradiotherapy (CRT). However, the efficacy of adding nivolumab to neoadjuvant CRT remains unclear. Methods: We conducted a phase II trial of neoadjuvant nivolumab (240mg IV on D-14, 1, 15, 29), paclitaxel (50mg/m2 IV on D1, 8, 15, 22, 29), cisplatin (30mg/m2 IV on D1, 8, 15, 22, 29) and RT (45Gy given in 25 fractions) followed by esophagectomy 6 to 8 weeks after finishing CRT in pts with locally advanced ESCC, defined as clinical stage cT3-4aN0M0 or cT1-3N1-3M0 according to the AJCC Cancer Staging System 8th ed. (ClinicalTrials.gov Identifier: NCT05130684). The study, in a Simon’s two-stage design, used pathological complete response (pCR) rate as the primary endpoint. Secondary endpoints included feasibility, safety, recurrence free survival (RFS), progression free survival (PFS), and overall survival (OS). Results: Between Jan 2021 and Apr 2023, we enrolled a total of 17 pts. Fifteen were male. The median age was 52 years (range: 44~69). The clinical stage was I, II, and III in 1, 1, and 15 pts, respectively. All pts received neo-NTP-CRT with the following dose-intensities (mean dose intensity [range]): nivolumab (95% [50%~ 100%]), paclitaxel (75% [48%~ 100%], cisplatin (97% [80%~ 100%]), and radiotherapy (100%). Fourteen pts received esophagectomy, and 4 of them achieved pCR (24%). Because pCR for the first stage did not meet the efficacy criteria to move forward to second-stage, the enrollment was discontinued after enrolling 17 pts. During neo-NTP-CRT, the most common treatment-related adverse events (TRAEs) were leukopenia (76%), neutropenia (59%), thrombocytopenia (35%), and skin rash (35%); and the most common grade 3 and 4 TRAEs were leukopenia (24%), neutropenia (6%), and nausea and vomiting (6%). Among 14 pts receiving esophagectomy, 4 experienced surgical complications, including 2 with anastomotic leakage, 1 with subclavian artery rupture, and 1 with pneumonitis; one pt died 263 days after surgery, followed by a prolonged hospital stay due to refractory anastomotic leakage, infectious complications, and tumor progression. The median follow-up duration was 18 months. Median RFS, PFS and OS was 8, 12, and 16 months, respectively. Conclusions: Our data indicate that adding nivolumab to neoadjuvant paclitaxel and cisplatin-based CRT is feasible but does not improve pCR rate in locally advanced ESCC pts. Clinical trial information: NCT05130684 .