Cancer Therapy Research Articles

Multiomic analysis uncovers a continuous spectrum of differentiation and Wnt-MDK-driven immune evasion in hepatoblastoma.

Hepatoblastoma is the most common pediatric cancer of the liver and the majority of cases display activating mutations in the Wnt/β-catenin pathway. Understanding the complex milieu of the tumor microenvironment has resulted in promising new therapies for adult cancers, but similar approaches in pediatric cancers are still lacking. We aimed to provide a comprehensive analysis of the tumor microenvironment of hepatoblastoma unveiling its spatial architecture and key signaling mechanisms. Single-cell/-nucleus RNA-seq (n=15), spatial transcriptomics (n=22), and multiplex immunofluorescence stainings (n=7) of treated, untreated, and metastasized pediatric hepatoblastomas were performed. An RNA-seq validation cohort (n=110) including hepatoblastoma, non-tumor and fetal liver samples and single-cell RNA-seq data of healthy immune cells were used for further analysis. Western blotting and RNA-seq of hepatoblastoma and macrophage cell lines were conducted for experimental validation. Of four identified transcriptional tumor programs, "Developmental" and "Metabolic" reflected different hepatic differentiation stages, while "Cycling" was enriched in undifferentiated cells and relapsed samples, and "Intermediate" displayed high activity in samples from patients with poor outcomes. We discovered an increased ratio of anti- to pro-inflammatory immune cells and evidence of immune exclusion from tumor areas. Wnt-responsive upregulation of the immunomodulator midkine in hepatoblastoma cells was associated with a change in macrophage phenotype, which could be partially reversed through midkine inhibition. Hepatoblastoma cells exist along a continuous spectrum of hepatic differentiation and inhabit an altered immune environment. Wnt signaling augments midkine expression, which appears to be involved in shaping the immune environment by modifying macrophages to enable immune evasion, thereby providing a potential therapeutic target. Despite hepatoblastoma being the most common pediatric liver cancer, there has been a critical knowledge gap in understanding how the tumor microenvironment and immune landscape contribute to disease progression. Our novel findings, revealing a continuous spectrum of tumor differentiation states and Wnt-MDK-driven immune evasion, are significant for pediatric oncology clinicians and researchers, improving our functional understanding of the immune environment of hepatoblastoma. The identification of midkine as a tumor-specific immunomodulator suggests a potential for developing new targeted therapies, though further mechanistic and practical validation would be needed to realize clinical translation of these findings.

Acquired gene alterations potentially related to resistance to anti-HER2 therapy in HER2-positive metastatic colorectal cancer (mCRC).

277 Background: While HER2-targeted therapies benefit patients (pts) with advanced HER2-positive mCRC, the development of resistance remains inevitable. This study aims to explore the landscape and frequency of genetic alterations putatively associated with acquired resistance to anti-HER2 therapy in HER2-positive mCRC. Methods: In this retrospective-multicenter international study involving Mayo Clinic, Duke Cancer Center and National Cancer Center Hospital East (Japan), we descriptively compared comprehensive genomic analyses from tissue or blood samples of pts with HER2-positive CRC pre-treatment and post-treatment with HER2-targeting agents. Results: A total of 36 pts were included in this study. 29 (80%) had HER2-positive mCRC as confirmed by immunohistochemistry (IHC) and fluorescent in situ hybridization (ISH), the remaining pts had HER2 amplification detected on blood or tissue . 34/36 (94%) pts were administered their first anti-HER2 agent after progressing on ≥2 prior lines of treatment. The most common anti-HER2 regimen administered was trastuzumab/pertuzumab (50%, 18/36), followed by trastuzumab-tyrosine kinase inhibitors (TKIs) (tucatinib or neratinib) (30%, 11/36) and trastuzumab deruxtecan (14%, 5/36). Putative genomic mechanisms of acquired resistance were detected in 72% (26/36), while the remaining pts lacked new genomic alterations that might explain resistance to anti-HER2 therapy, suggesting alternative escape mechanisms. Acquired alterations in downstream or alternate bypass pathways were identified in 72% (26/36) of pts; most commonly in the RAS/RAF pathway and in EGFR (34.6%, 9/26 each), followed by 27% (7/26) of pts with MET point mutations (mts) and amplification; activating muts in PI3K/AKT and in 27% (7/26), most commonly CDK12 (60%, 4/7) . HER2 receptor alterations were detected in 3 pts (8.3%), all of whom received trastuzumab-tucatinib and included HER2 L755S, HER2 V777L, HER2 D769Y, HER2 G727A and HER2 S310F, which are known to cause resistance to , however, information about tucatinib resistance is not yet available. Other altered pathways included AR, RB, NOTCH and HRD. Two pts lost HER2 expression on blood and tissue NGS post anti-HER2 therapy. Conclusions: The emergence of resistance might be in part related to acquired alterations that constitutively activate signaling pathways parallel or downstream of HER2, bypassing HER2 inhibition. Additional histologic studies, deep mutational scanning, larger populations and correlative analysis are needed to validate these findings.

Self-assembled nanodrug based on ferroptosis inducer and sonosensitizer for enhanced sonodynamic-triggered multimodal synergistic therapy of prostate cancer

Self-assembled nanodrug based on ferroptosis inducer and sonosensitizer for enhanced sonodynamic-triggered multimodal synergistic therapy of prostate cancer

Unlocking the potential: FKK6 as a microbial mimicry-based therapy for chronic inflammation-associated colorectal cancer in a murine model

Unlocking the potential: FKK6 as a microbial mimicry-based therapy for chronic inflammation-associated colorectal cancer in a murine model

Adjuvant chemotherapy or chemo-radiation in gallbladder cancer: A phase III randomized controlled study (ACCELERATE trial).

519 Background: Role of adjuvant therapy in gallbladder cancer is still evolving and no prospective trial has compared chemotherapy (ChT) alone to combination of chemotherapy and chemo-radiation (CRT). We designed this trial to answer whether adding CRT to ChT improves relapse free survival. Methods: In this open-label, multicentric, phase 3, non-inferiority academic trial, operated gallbladder cancers (R0 or R1) patients were randomized to physicians choice of ChT alone (either 6 cycles of mGemOx- Gemcitabine 900 mg/m2 and oxaliplatin 80 mg/m2 IVI days 1 and 8 every 3 weeks or GemCis- Gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 1 and 8 every 3 weeks) or 3 cycles of physicians choice of ChT (as above) followed by CRT (radiation 45Gyin 25 fractions in 5 weeks with concurrent oral capecitabine in the dose of 825 mg/m2 twice a day on days of radiation and further 2-3 cycles of mGemOx or GemCis. The primary endpoint was the relapse free survival. Planned sample size was 100 subjects in each arm. Results: Between April 2018 and January 2021, 137 patients were screened, and 94 eligible patients were randomized, 49 (52.1%) in chemotherapy alone arm (standard-arm1) and 45 (47.9%) in chemotherapy plus chemo-radiation arm (experimental-arm 2). Slow accrual led to premature closure of trial. COVID pandemic might have contributed to that. Baseline characteristics were well balanced (like, sex, presenting symptoms, ECOG PS, duration of symptoms, comorbidities, location of tumour in GB, presence of gallstone disease, and tumour markers were well balance in both groups) except that a greater number of patients had deranged baseline LFTs in arm1 and there was a trend towards higher numbers of stage IIA in arm 1. The median age was 55 years (range 27-73 years). Females constituted 32 in each group. 43 and 45 patients had ECOG PS of 0-1 in arm 1 and arm 2 respectively. One patient in arm 1 was ineligible. All had R0 resection. Incidences of dose reductions and dose delays were similar. A greater number of patients in arm 1 experienced diarrheal episodes (p=0.021) and peripheral neuropathy (0.001). 42 (85.7%) patients in arm 1 and 28 (62.2%) patients in arm completed 5-6 cycles. 18 (36.73%) and 23 (51.11%) died till last follow up. 14 (28.57%) and 20(44.44%) died because of disease progression. One patient in each arm died of toxicity. The primary end point of study, relapse free survival was not estimable in arm 1 and was 34.39 months in arm 2 (p=0.202). Median overall survival was not estimable in arm 1 and was 34.56 months in arm 2 (p=0.123). Mean RFS was 51.96 Vs 43.99 months in arm 1 and arm 2 respectively. Conclusions: This trial suggests that addition of CRT to ChT doesn’t improve outcome in resected gallbladder cancer compared to ChT alone. A larger trial is needed to address this issue. Clinical trial information: CTRI/2018/04/013218.

Bevacizumab plus mFOLFOX6/FOLFIRI sequential bevacizumab plus capecitabine maintenance in RAS-mutated advanced colorectal cancer: A real-world study of first-line/second-line conversion therapy.

77 B ackground: Currently, the standard first-line/second-line treatment for advanced colorectal cancer with RAS mutations is chemotherapy combined with bevacizumab. Patients with colorectal cancer confirmed maintenance therapy can effectively improve progression-free survival, improve patient quality of life. Therefore, this study aims to evaluate the efficacy and safety of bevacizumab combined with mFOLFOX6/FOLFIRI sequential bevacizumab combined with capecitabine as first-line/second-line conversion therapy for RAS-mutated advanced colorectal cancer. M ethods: This is an open-label, single-center study in previously untreated patients with RAS mutant mCRC. Eligible patients received first-line chemotherapy of bevacizumab (5mg/m 2 ) combined with mFOLFOX6/FOLFIRI for 12 cycles randomly, during which the efficacy was assessed every 4 cycles, then followed by bevacizumab(7.5mg/m 2 ) in combination with capecitabine maintenance therapy which assessed every 2 cycles until disease progression, and then switched to the second-line therapy FOLFIRI/mFOLFOX6 combined with bevacizumab which was assessed every 4 cycles until disease progression or intolerable toxicity. Imaging studies were performed to assess treatment efficacy according to RECIST1.1 criteria, and the primary endpoint was progression-free survival (PFS), including first-line PFS and second-line PFS after progression, and the secondary endpoints included disease response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. R esults: This study recruited 78 subjects from January 2021 to May 2024. As of September 10, 2024, a total of 70 subjects were analyzable for the first-line treatment, of which 6 subjects met the surgical criteria after treatment and achieved NED status; 45 patients reached the first-line PFS endpoint, with a median PFS (mPFS) of 249 days (95% CI: 204.4-293.6), an ORR of 38.6%, and a DCR of 95.7% . Twenty patients entered the first-line maintenance therapy, with a mPFS of 358 days (95% CI: 53.8-662.2). For the second-line treatment, a total of 43 subjects were analyzable, of which 35 patients reached the second-line PFS endpoint, with a second-line mPFS of 171 days (95% CI: 89.8-252.1). 41 subjects underwent at least one efficacy evaluation, with ORR of 14.6% and DCR of 75.6%. The most common grade 3 treatment-related adverse events were neutropenia, leukopenia, anemia, hypertension, diarrhea, and thrombocytopenia. There were no treatment-related deaths. No new adverse events occurred during the entire combination treatment period. C onclusions: This real world study has demonstrated good tolerability and encouraging clinical efficacy, especially with potential implications for treatment planning and management strategies for advanced colorectal cancer with RAS mutations. Clinical trial information: ChiCTR2100042553 .

Efficacy of hydrogel spacer compared with intensity-modulated radiotherapy for 3-dimensional conformal radiotherapy for prostate cancer.

One major adverse effect of prostate radiotherapy is associated with the rectum. The SpaceOAR system has been developed to address this problem, as it enables treatment planning with a reduced dose to the rectum. This study aimed to evaluate and compare the treatment plans between three-dimensional conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT) for prostate cancer using the SpaceOAR system. Thirty-five patients treated with prostate cancer radiation using the SpaceOAR system received a total radiation dose of 60 Gy/20 fractions. The dose constraints and robustness of the plan for VMAT and 3D-CRT were compared. For 3D-CRT, 6-field conformal method and 2-arc conformal method were created and compared in 3 treatment plans together with VMAT. The dose-constraint evaluation was performed using the planning target volume (PTV), rectum (mean dose), bladder (mean dose), and femoral head (mean dose). One issue associated with prostate radiotherapy is the physiological movement of the target prostate gland, which reduces the accuracy of irradiation. The prostate moves several millimeters during irradiation due to physiological movements, and there are reports of a decrease in the PTV index due to this effect. This has a significant impact on the cure rate of prostate cancer. A comparative study of the 3 irradiation methods was conducted to investigate this issue. Each study item was analyzed using the Friedman test to determine the significance of the 3 irradiation methods. Our analysis showed that the dose constraint was statistically significant for VMAT, but 3D-CRT was also sufficient in achieving dose constraints. The hydrogel spacer reduced the rectal dose and improved the dose-constrained fulfillment rate in VMAT and 3D-CRT. In a study of prostate motion during irradiation, 3D-CRT, a robust plan, was superior in the PTV mean evaluation over VMAT, where the multileaf collimator moved in fine increments. VMAT is currently the standard treatment for prostate cancer; however, with the introduction of the SpaceOAR system using hydrogel spacers, 3D-CRT may also be a viable option for prostate cancer treatment.

Optimal timing for Initiating First-Line Palliative Systemic Therapy in Asymptomatic Metastatic Esophagogastric Cancer: Insights from a European Delphi study

Optimal timing for Initiating First-Line Palliative Systemic Therapy in Asymptomatic Metastatic Esophagogastric Cancer: Insights from a European Delphi study

Real-world evidence of nanoliposomal irinotecan and fluorouracil with folinic acid in patients with unresectable or recurrent pancreatic cancer: Final results of a multicenter observational study.

721 Background: Nanoliposomal irinotecan (NAL-IRI) and fluorouracil with folinic acid (NFF) is the standard regimen after gemcitabine-based therapy for unresectable or recurrent pancreatic cancer (urPC). However, we have almost no prospective data on its efficacy and safety in the real-world, so we conducted this study to investigate them both retrospectively and prospectively (NAPOLEON-2 study). We previously reported the retrospective data in ASCO-GI 2023, and here we report the final results of the prospective part. Methods: We prospectively collected data of urPC patients treated with NFF who had received at least one previous chemotherapy line in 17 hospitals in Japan from June 2021 to October 2023. The primary endpoint was overall survival (OS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), dose intensity (DI) and adverse events (AEs). In addition, OS and PFS among the therapeutic lines of NFF were also analyzed. Results: A total of 150 urPC patients were prospectively enrolled. The median follow-up period was 7.2 months (95% confidence interval [CI], 6.3–8.8); median age, 72 years (range, 45–85), with 81 female patients (54%). The Eastern Cooperative Oncology Group performance status was 0/1/2/3 in 46/93/10/1 patients, respectively. Sixteen patients (11%) had locally advanced disease; 134 (89%) had metastatic disease; 77 (51%) had liver metastasis; and 47 (31%) had peritoneal metastasis. All patients previously received gemcitabine-based therapy. NFF was administered as 2nd/3rd/4th-or-later-line therapy to 87/53/10 patients, respectively. The median OS was 7.8 months (95% CI, 6.6–9.2); median PFS, 3.7 months (95% CI, 2.8–4.9); overall response rate, 11%; and disease control rate, 56%. The relative dose intensity was 72.7% with NAL-IRI and 79.4% with fluorouracil. The initial dose of NAL-IRI was reduced in 84 patients (56%), mainly owing to decreased organ function (17%), followed by age (12%), worsened performance status (10%), or UGT1A1 examination status (5%). Dosage reduction of NAL-IRI during treatment (independent of the initial dose reduction) was performed in 74 patients (49%), mainly owing to neutropenia (22%) and anorexia (11%). Frequent Grade 3/4 adverse events were neutropenia (27%), anorexia (19%), and leukopenia (16%). Grade 5 peritoneal infection was observed in only one patient. The median OS and PFS for NFF in the 2nd-line group, compared with the 3rd-or-later-line group, were 7.4 vs 7.8 months (hazard ratio [HR], 0.97; 95% CI, 0.68–1.39; p=0.88) and 3.3 vs 4.2 months (HR, 1.04; 95% CI, 0.74–1.45; p=0.84), respectively. Conclusions: NFF had appropriate efficacy and manageable toxicity profiles, consistent with our previous report. NFF can be a candidate for 2nd-or-later-line regimens in the real-world. Clinical trial information: UMIN000043939 .

Prediction of the need of enteral nutrition during radiation therapy for head and neck cancers.

Patients with a head and neck (HN) cancer undergoing radiotherapy risk critical weight loss and oral intake reduction leading to enteral nutrition. We developed a predictive model for the need for enteral nutrition during radiotherapy in this setting. Its performances were reported on a real-world multicentric cohort. Two models were trained on a prospective monocentric cohort of 230 patients. The first model predicted an outcome combining severe or early fast weight loss, or severe oral intake impairment (grade 3 anorexia or dysphagia or the prescription of enteral nutrition). The second outcome only combined oral intake impairment criteria. We trained a gradient boosted tree with a nested cross validation for Bayesian optimization on a prospective cohort and predictive performances were reported on the external multicentric real-world cohort of 410 patients from 3 centres. Predictions were explainable for each patient using Shapley values. For the first and second outcome, the model yielded a ROC curve AUC of 81% and 80%, an accuracy of 77% and 77%, a positive predictive value of 77% and 72%, a specificity of 78% and 79% and a sensitivity of 75% and 73%. The negative predictive value was 80% and 80%. For each patient, the underlying Shapley values of each clinical predictor to the prediction could be displayed. Overall, the most contributing predictor was concomitant chemotherapy. Our predictive model yielded good performance on a real life multicentric validation cohort to predict the need for enteral nutrition during radiotherapy for HN cancers.

A phase 2 study of amplitude-modulated radiofrequency electromagnetic fields (AM RF EMF) in metastatic pancreatic cancer.

TPS790 Background: Patients with advanced pancreatic adenocarcinoma (PDC) that progresses after first-line therapy face limited treatment options. Despite advances in systemic therapy, the prognosis for PDC is dismal, with a five-year overall survival (OS) of about 5% . Due to the high morbidity of this disease, there is a critical need for innovative treatments to improve patient outcomes. TheraBionic P1, a hand-held device, delivers tumor specific radio frequencies via a spoon-shaped antenna placed on the patient's tongue. The FDA and EMA have confirmed the safety of the device for amplitude-modulated electromagnetic field (AM-EMF) therapy. Improved efficacy outcomes were reported with AM RF EMF in other solid organ tumors including pancreatic cancer in preliminary studies. Preclinical and clinical evidence suggests that AM-EMF can inhibit tumor growth and was recently approved for use in hepatocellular cancer. The safety and clinical activity observed with AM RF EMF, paired with the unmet medical need for additional effective therapies in pancreatic cancer, provided a strong rationale for further clinical investigation. This protocol evaluates the efficacy and tolerability of AM RF EMF in combination with standard of care frontline therapy, gemcitabine and nab-paclitaxel for metastatic PDC. Methods: This is an ongoing, single-center, Phase II, non-randomized study using a Simon two-stage minimax design to assess the efficacy of AM-EMF in combination with gemcitabine/nab-paclitaxel as a first-line treatment in metastatic pancreatic cancer. Gemcitabine and nab-paclitaxel are administered per standard care. AM RF EMF are delivered to patients with a spoon-shaped applicator placed on the tongue three daily 60-minute treatments. Patients will be assessed for response every 8 weeks. Treatment is continued until progression or toxicity. The primary objective of this study is to evaluate the efficacy of the combination of nab-paclitaxel, gemcitabine, and AM RF EMF in improving 6-month overall survival rates in patients with metastatic PDC. Secondary objectives evaluate the safety, tolerability, profession free survival, objective response rate and disease control rate. Exploratory objectives evaluate change in CA19-9 and quality of life using FACT-General (FACT-G) and determine any possible correlation with clinical outcomes. Key eligibility includes treatment-naïve, histologically confirmed metastatic PC, age eighteen years old or greater, ECOG 0-1, and optimal organ function. Clinical trial information: NCT05776524 .

Antibody-drug conjugates (ADCs): a novel therapy for triple-negative breast cancer (TNBC).

NA.

Safety and efficacy of conversion therapy for metastatic esophageal cancer: Exploratory analysis of JCOG1314.

401 Background: Patients with esophageal cancer (EC) with distant metastasis were treated with systemic chemotherapy. Recent advances in multimodal treatments have made conversion therapy (CT) a viable option for patients with metastatic EC. JCOG1314 was a randomized phase III trial to confirm the survival benefit of docetaxel plus cisplatin plus 5-fluorouracil (DCF) versus cisplatin plus 5-fluorouracil (CF) as initial treatment for unresectable or recurrent esophageal cancer. The purpose of this study was to evaluate the safety and survival impact of CT in patients enrolled in JCOG1314. Methods: CT was defined as surgery or chemoradiotherapy (CRT) aiming at cure after initial treatment for tumors that were initially unresectable due to distant metastasis. Clinicopathologic factors, surgical outcomes, toxicities during CRT, and survival were compared between CT and non-CT groups. CTCAE v4.0-JCOG was used to evaluate postoperative complications and adverse events during CRT. Results: Between September 2014 and April 2021, 240 patients were randomized to CF or DCF. Excluding patients with recurrent disease, 154 patients with initially unresectable esophageal cancer due to distant metastasis were selected for this study. Among them, 21 patients received CT which included conversion surgery (n=5) and conversion CRT (n=16). There was no significant difference in the number of metastatic organs, depth of invasion of the primary tumor, lymph node metastasis, and chemotherapy regiment between CT and non-CT groups. The most common M1 factor in CT group was the thoracic lymph node, followed by abdominal lymph node and cervical node. In conversion surgery group, there was no incidence of Grade 3 or higher pneumonia/leakage. Regarding the Grade 3 or higher non-hematological toxicities during conversion CRT, the incidence of appetite loss/ oral mucositis/pneumonia was 2 (13%)/2 (13%)/1 (6%), respectively. The 3-year overall survival (OS) of CT and non-CT groups was 52.4% and 14.3%, respectively. On multivariable analysis, patients with CT showed significantly better OS compared with the non-CT group (HR 0.36, 95% CI 0.19-0.67, p<0.01). In patients who underwent CT, there was no significant difference in OS between conversion surgery and CRT groups. Conclusions: This study demonstrated that CT was safely performed with favorable prognosis. A prospective study is warranted to investigate whether CT would improve survival in metastatic esophageal cancer.

Pan-cancer analysis of DCBLD1 and its association with the diagnosis, immunotherapy, and prognosis of cervical cancer.

Cervical cancer (CESC) is a leading cause of death attributed to cancer worldwide. Advanced-stage cervical cancer presents unique challenges, such as few treatment modalities. Though DCBLD1 has been earlier connected to a variety of cancers, there has been no extensive investigation on DCBLD1 regarding cervical cancer. This study seeks to assess the expression and prognostic significance of DCBLD1 in multiple cancer types, heavily relying on cervical cancer, as well as its implications on immune modulation. The pan-cancer expression of box-like genes in DCBLD1 was investigated in 33 cancer types using The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE). Survival analyses involving Overall Survival (OS) and Progression-Free Survival (PFS) were conducted to evaluate the relationship between DCBLD1 expression and the prognosis of these neoplasms. Furthermore, immune infiltration gene co-expression and tumor microenvironment (TME) analyses were performed. In vitro assays in cervical cancer cell lines were done to analyze the functional impact of silencing DCBLD1 on cell proliferation, migration, and invasion. DCBLD1 was significantly overexpressed in 16 cancer types, including cervical cancer, and was associated with poor prognosis for several of these cancer types. In CESC, the expression of DCBLD1 was significantly associated with shorter OS and PFS. While immune infiltration analysis showed a significant association for DCBLD1 with several immune cells, including CD4+ memory T cells and macrophages, the functional assays demonstrated that silencing DCBLD1 in cervical cancer cells inhibited their cell proliferation, migration, and invasion, implicating it in tumor progression. DCBLD1 could serve as an amendable biomarker of poor prognosis in cervical cancer and other cancers whose high expression level correlates with immune infiltration, which may suggest its role in modulating the tumor microenvironment. This shows that targeting DCBLD1 could prove effective as a potential therapeutic modality in conjunction with other immune-based therapies for cervical cancer.

Nelmastobart (hSTC810) combined with capecitabine therapy in metastatic colorectal cancer with resistance or intolerance to oxaliplatin and irinotecan-based chemotherapy: A phase 1b clinical trial.

162 Background: Treatment options for patients with metastatic colorectal cancer (mCRC) who experienced disease progression after receiving oxaliplatin and irinotecan-based chemotherapy are limited. Nelmastobart (hSTC810), a humanized anti-BTN1A1 (butyrophilin subfamily 1 member A1) monoclonal antibody of the IgG4 isotype, showed acceptable safety profile and the disease control rate was 39.3% in the first-in-human study, suggesting its potential efficacy. This phase Ib study was designed to evaluate the safety and explore synergistic anti-tumor activity of nelmastobart in combination capecitabine. The study aims to determine the maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of this combination therapy in patients with mCRC who are refractory to standard therapy. Methods: Dose escalation phases were conducted in patients with mCRC who were administered orally twice daily capecitabine (850mg, 1000mg, 1250mg orally, days 1-14) and nelmastobart (400mg, 800mg intravenously every 3 weeks). Standard "3 + 3" dose escalation was used to define the MTD. In this phase 1b, 12 participants enrolled between February 5 2024 and June 11 2024 were 18 years of age or older with mCRC previously treated oxaliplatin and irinotecan in the metastatic setting. Results: The first 3 patients at the dose level 0 (nelmastobart 400mg, capecitabine 1,000 mg/m 2 twice daily) and level 1 (nelmastobart increased to 800 mg, capecitabine 1,000mg/m 2 twice daily) had no dose-limiting toxicities (DLTs). In dose level 2 (nelmastobart 400mg, capecitabine 1,250mg/m 2 twice daily), 2 of 3 had DLTs (grade 3 hand-foot syndrome), which were attributed to capecitabine. When dose level 2 was expanded to 3 additional patients, 2 more patients experienced DLTs (grade 3 mucositis and hand-foot syndrome). Consequently, the combination of nelmastobart 800 mg once every three weeks and capecitabine 1,000 mg/m² twice daily (2 weeks on 1 week off) was established as the MTD/RP2D in patients with mCRC. The most common AEs were hand-foot syndrome (n=4), nausea (n=3) and stomatitis (n=2) which were related with capecitabine. Four patients experienced grade 1 fatigue, which was considered to be related to nelmastobart. Two patients (16.7%) out of 12 showed partial response and 8 patients have maintained stable disease for more than 4 months among 9 patients who had a median follow-up of more than 4 months (as of August 30). Conclusions: The combination of hSTC810 and capecitabine is well tolerated at the MTD, without unexpected AEs and shows promising antitumor activity in patients with heavily treated mCRC. The phase 2 study is currently in progress. Clinical trial information: NCT0599054 .

Phase II study of niraparib and dostarlimab for the treatment of germline or somatic homologous recombination repair mutated (HRD) metastatic pancreatic cancer.

727 Background: PARP inhibition (PARPi) is a standard maintenance therapy for patients (pts) with germline BRCA1/2 mutations in pancreatic cancer. Combination of PARPi therapy and immunotherapy has potential to increase efficacy and may offer benefit beyond germline BRCA1/2 . Methods: We performed a multisite single-arm phase 2 study using the highly potent PARPi niraparib with anti-PD1 drug dostarlimab in pts with germline or somatic HRD mutations in BRCA1/2, PALB2, RAD51C/D, or BARD1 . Pts were required to have metastasis, progressed on ≥1 regimen, and prior platinum-exposure unless refused/intolerant. Pts were treated with niraparib 200 mg orally once daily continuously. Dostarlimab 500 mg was administered IV every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks. The primary endpoint was disease control rate (DCR) at 12 weeks (DCR12) using iRECIST criteria. At least 8 pts with DCR12 in the first 19 eligible pts (41%) would be considered promising for further trials. Results: 22 pts were enrolled from Dec 2020 to Oct 2023. Two pts withdrew prior to receiving therapy, and 2 were later found to be ineligible, leaving 18 eligible pts for final analyses. Median age was 63.0 yrs, 39% male, 94% non-Hispanic white, 1 black (6%). 17 pts were platinum exposed, 7 were platinum-refractory, and 5 had previously progressed on PARPi maintenance. Mutation distribution was: BRCA2 13/18 (72%), BRCA1 4/18 (22%), BARD1 2/18 (11%). One pt had both BRCA1 (somatic) and BRCA2 (germline) mutations. Germline mutations were identified in 14/18 (78%). DCR12 was achieved in 5/18 (27.8%), so the primary endpoint (>41%) was not met. Pts received a median 2 cycles (range 1-8) of niraparib + dostarlimab. No clinical factors were significantly associated with improved DCR12 (all p > 0.05) in subgroup analyses, but we did observe the following statistically nonsignificant associations. Pts who were platinum-refractory had a lower DCR12 compared to those not (14.3% vs. 36.4%). Counterintuitively, PARPi exposed/refractory pts had a higher DCR12 than non-exposed/non-refractory (50 vs 17% exposed/nonexposed and 40% vs 23% refractory/nonrefractory). Pts with germline mutations had a higher DCR12 compared to those without (38.5% vs. 0%). Non- BRCA2 mutations had a higher DCR12 than those with BRCA2 mutations (50% vs.17%), with highest DCR12 rates among BRCA1 patients (67%). Tolerability was in line with similar combinations, with 60% non-hematologic Gr3 or higher, including fatigue (15%), AST increase (10%), nausea/vomiting (10%), sepsis (10%). Two grade 5 events were not attributed to treatment. Conclusions: PARPi plus anti-PD1 checkpoint inhibition was not sufficiently active as later line therapy in metastatic pancreatic cancer for the majority of patients with HRD mutations. Additional molecular analyses to elucidate predictive markers of sensitivity/resistance are ongoing. Clinical trial information: NCT04493060 .

Neoadjuvant therapy in T3 and T4 colon cancer: Is there a promising future?

144 Background: Neoadjuvant chemotherapy (NAC) is increasingly being considered over standard upfront surgery followed by adjuvant chemotherapy for locally advanced colon cancer. Studies have been underpowered to look at the impact of NAC on overall survival (OS) in individual clinical T stages. Methods: A nationwide retrospective analysis using the National Cancer Database to evaluate patients with clinical stage T3 and T4 colon adenocarcinomas from 2010 to 2020. Cox proportional hazards model was used to evaluate the impact of NAC approach compared to upfront surgery on OS. Clinical and pathological T stages were compared among those who underwent upfront surgery to evaluate accuracy of clinical T staging. Results: Total of 60,557 patients were identified - 2,313 patients undergoing NAC and 58,245 undergoing upfront surgery. In the past decade, use of NAC increased from 1.73% to 12.13%. In our multivariable survival analysis combining clinical T3 and T4 patients, we observed a worse OS in the NAC group (HR 1.16, 95% CI 1.07-1.26). We found no OS benefit for patients undergoing NAC approach for clinical stage T3 (HR 1.13, 95% CI 0.99-1.28) but found a significant OS benefit for patients undergoing NAC approach for clinical stage T4 (HR 0.85, 95% CI 0.77-0.95). We observed that clinical T4 stage was accurately staged in 90.48% with overstaging in 9.52%; clinical T3 stage was accurately staged in 95.24% with overstaging in 2.18% of patients. Conclusions: Our analysis demonstrated OS benefit of the NAC approach in T4 colon adenocarcinoma but not in T3. The study highlights the importance of evaluating survival benefit of NAC separately for T3 and T4 colon adenocarcinoma in future studies, and the challenges of accurate clinical staging of colon cancer for NAC planning.

A retrospective study of the prognostic value of early induction of S-1 postoperative adjuvant therapy for pancreatic cancer.

689 Background: The usefulness of oral S-1 administration as adjuvant therapy (AC) after pancreatic cancer surgery has been demonstrated (1). Our study also suggested the importance of maintaining relative dose intensity or postoperative early induction (2). In a large Japanese data set, a comparison of induction before and after the postoperative 10 weeks showed a worse prognosis in the group which started 10 weeks after surgery (3). However, the number of patients of which early induction is possible are gradually increasing with recent improvements of surgical outcomes. In the present study, we retrospectively evaluated the survival benefit of AC which was started within 2 weeks after surgery. Methods: 129 patients with invasive pancreatic cancer who underwent radical surgery from January 2018 to May 2023 were enrolled in this retrospective study. The patients were divided into the following groups: 46 (36%) underwent induction within 2 weeks, 56 (43%) within 3-6 weeks, 13 (10%) after 7 weeks, and 14 (10%) without AC (4 with low renal function, 4 with deteriorating physical condition after surgery, 4 with not desired, and 2 with comorbid disease treatment). The background of each group was as follows (Described in the following order; induction within 2 weeks after surgery: 3-6 weeks: after 7 weeks: without AC), age 71: 71: 71: 78 (n.s.), pancreatic head cases 52: 68: 69: 50% (n.s.), BR cases 35: 23: 8: 21% (n.s.), NAC performed 86: 38: 15: 29% (p < 0.001), preoperative CEA ≥ 5.0ng/ml 24: 23: 8: 21% (n.s.), preoperative CA19-9 ≥ 37U/ml 48: 52: 54: 64% (n.s.), PV/SMV reconstruction 20: 16: 31: 14% (n.s.), postoperative complications (Clavien Dindo ≤3) 0: 16: 31: 43% (p < 0.001), Pathological stage 2 or higher 83: 65: 77: 79% (n.s.). Results: The need for reduction of S-1 dosage was 87: 89: 92% of the patients (n.s.), and the 6-month completion rate was 70: 71: 61% (n.s.). Median overall survival duration in each group was as follows: not reached: 49.5: 35.5: 48.6 months, and 1-year postoperative recurrence-free survival was 73: 66: 45: 71%, median recurrence free survival time was 34.0: 20.8: 10.3: 12.1 months, and induction within 2 weeks after surgery group significantly improved the recurrence-free survival in comparison with the group of after 7 weeks (p < 0.05). No significant factors were detected in multivariate analysis. Conclusions: These results suggest that early induction of AC as a result of improvement of surgical outcomes would contribute to postoperative recurrence-free survivals. 1. Uesaka et al, Lancet, 2016. 2. Matsushima et al. Anticancer Res, 2022. 3. Tomimaru et al, J Gastroenterol, 2023.

Correlation of mesothelin (MSLN) expression measured by RNA sequencing (RNASeq) and immunohistochemistry (IHC) in MSLN-expressing tumors.

766 Background: BASECAMP-1 (NCT04981119) is a pre-screening study to identify patients with tumor-associated human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH) for interventional studies, such as EVEREST-2 (NCT06051695), a phase 1/2 study of logic-gated chimeric antigen receptor T-cell (CAR T) therapy for MSLN-expressing cancers. MSLN is a cell surface protein expressed in several cancer types, including mesothelioma (MESO), colorectal (CRC), non-small cell lung (NSCLC), ovarian (OVCA), and pancreatic (PANC) cancer, which can be associated with poor prognosis (1). Longitudinal clinical, genomic, and biomarker data were collected from patients enrolled in BASECAMP-1, providing a large dataset for translational discovery and propensity scoring. The aim of this analysis was to determine whether MSLN expression measured by RNAseq and IHC are correlated among patients with solid tumors. Methods: In BASECAMP-1, tumor tissue from patients with germline heterozygous HLA-A*02 is tested for HLA-A*02 LOH using an investigational next generation sequencing device codeveloped with Tempus Labs (Lozac'hmeur, et al. NPJ Precis Oncol. 2024) that detects somatic alterations, including HLA LOH, and generates RNAseq data (eg, MSLN expression). Gene-level transcripts per million read (TPM) values were determined and the log2 TPM +1 was displayed in a scatter plot (the mean and standard deviation [SD] are provided in the Table). Patients with HLA-A*02 LOH also submit tissue for IHC testing for exploratory biomarkers (eg, MSLN expression using anti-MSLN clone 5B2). Statistical significance was determined with ANOVA or t-tests. Results: As of June 1, 2024, 314 patients had been screened for BASECAMP-1 and had RNAseq results; 34 patients also had MSLN IHC results. MSLN expression by RNAseq was consistently higher in patients with PANC or OVCA vs CRC or NSCLC ( P <0.001). MSLN expression by RNAseq and IHC were correlated overall ( P <0.001), particularly among patients with PANC and OVCA. Among the 8 patients with OVCA or PANC who were IHC+ for MSLN, only 1 had an RNAseq value below 6 log2 TPM+1; this patient had mesonephric-like ovarian adenocarcinoma, which may account for the low value. The one MESO sample with both RNAseq and IHC available was IHC+ and had a high RNAseq value. Conclusions: This analysis demonstrated high correlation between RNAseq and IHC MSLN expression in tumor tissue. 1. Faust, et al. Cancers. 2022. Clinical trial information: NCT04981119 . MSLN expression by RNASeq by tumor type and IHC status. Tumor Overall (N=314) IHC data available (n=34) MSLN Positive MSLN Negative n Mean TPM a (SD) n Mean TPM a (SD) n Mean TPM a (SD) All 314 5.1 (2.3) 20 6.0 (2.1) 14 2.3 (1.7) adNSCLC 33 3.8 (2.4) 2 4.7 (1.7) 7 1.5 (1.3) sqNSCLC 4 3.1 (1.8) 0 0 MESO 4 4.5 (4.2) 1 5.7 0 CRC 148 4.4 (2.0) 8 5.1 (2.1) 7 3.1 (1.6) PANC 100 6.1 (1.8) 3 7.8 (0.6) 0 OVCA 25 7.2 (2.1) 5 6.6 (2.8) 0 a MSLN log2 transcripts per million+1. ad, adenocarcinoma; sq, squamous.

Novel Therapies in Triple-negative Breast Cancer: Can less be More?

Novel Therapies in Triple-negative Breast Cancer: Can less be More?