Metastatic Solid Tumors Research Articles

Risk Factor Analysis of Complications and Mortality Following Coil Procedures in Patients with Intracranial Unruptured Aneurysms Using a Nationwide Health Insurance Database.

(1) Background: Unruptured intracranial aneurysm (UIA) occurs in 1-2% of the population and is being increasingly detected. Patients with UIA are treated with close observation, endovascular coiling or surgical clipping. The proportion of endovascular coiling has been rising. However, complications such as cerebral infarction (CI), intracranial hemorrhage (ICRH), and death remain crucial issues after coil treatment. (2) Methods: We analyzed the incidence and risk factors of complications after the use of coil in patients with UIA based on the patients' characteristics. We utilized the Health Insurance Review and Assessment (HIRA) database. Patients treated with coils for UIA between 1 January 2015 and 1 December 2021 were retrospectively analyzed. (3) Results: Of the total 35,140 patients, 1062 developed ICRH, of whom 87 died, with a mortality rate of 8.2%. Meanwhile, 749 patients developed CI, of whom 29 died, with a mortality rate of 3.9%. The overall mortality rate was 1.8%. In a univariate analysis of the risk factors, older age, males, a higher Charlson Comorbidity Index (CCI) score, and diabetes increase the risk of CI. Meanwhile, males with higher CCI scores and hemiplegia or paraplegia show increased ICRH risk. Older age, males and metastatic solid tumors relate to increased mortality risk. (4) Conclusions: This study is significant in that the complications based on the patient's underlying medical condition were analyzed.

Tumor-associated antigen targets for novel immune-based strategies in prostate cancer

Prostate cancer remains the most common malignancy among men in the United States. Advancements in androgen receptor signaling blockade have led to landmark approvals for its use in patients with locally advanced and metastatic disease. However, additional novel therapeutic strategies for both hormone-sensitive and castration-resistant diseases remain ongoing areas of study. Thus, we turn to the growth of immuno-oncology, which has led to improved treatment outcomes for a variety of hematologic and solid tumor malignancies. Prostate cancers have shown only modest results with immune checkpoint inhibition in published trials, and innovative strategies are now looking into enhancing cytotoxic T-cell activity against cancer cells. This review provides a thorough evaluation of tumor-associated antigens that are integrated into novel chimeric antigen receptor T-cell and bispecific T-cell engager therapies. Our review will evaluate the most recent advancements in immunotherapies, while also illustrating major obstacles and underlying limiting factors.

Hair depigmentation in a patient treated with pazopanib: A case report and a comprehensive analysis

Pazopanib is a multitargeted tyrosine kinase inhibitor used for the treatment of various solid tumor malignancies. Hair color change, particularly hair depigmentation, is a common side effect of pazopanib therapy. However, it usually develops gradually over a span of few months. This article will provide a comprehensive analysis of hair depigmentation in patients treated with pazopanib, focusing on the various aspects of this phenomenon, including its onset, possible causes, and potential implications for therapy success. Multitargeted tyrosine kinase inhibitors (MKIs) including pazopanib are recommended for various malignancies. Hair color changes are known side effects of MKIs. The exact mechanisms behind hair depigmentation due to pazopanib therapy are not yet fully understood. However, researchers believe that several factors may contribute to this phenomenon. We presented a case of a patient with relapse Ewings sarcoma who experienced rapid hair depigmentation during pazopanib therapy.

When Therapy-Induced Cancer Cell Apoptosis Fuels Tumor Relapse

Most therapeutic strategies for solid tumor malignancies are designed based on the hypothesis that cancer cells evade apoptosis to exhibit therapy resistance. This is somewhat surprising given that clinical studies published since the 1990s have demonstrated that increased apoptosis in solid tumors is associated with cancer aggressiveness and poor clinical outcome. This is consistent with more recent reports demonstrating non-canonical (pro-survival) roles for apoptotic caspases, including caspase 3, as well as the ability of cancer cells to recover from late stages of apoptosis via a process called anastasis. These activities are essential for the normal development and maintenance of a healthy organism, but they also enable malignant cells (including cancer stem cells) to resist anticancer treatment and potentially contribute to clinical dormancy (minimal residual disease). Like apoptosis, therapy-induced cancer cell dormancy (durable proliferation arrest reflecting various manifestations of genome chaos) is also not obligatorily a permanent cell fate. However, as briefly discussed herein, compelling pre-clinical studies suggest that (reversible) dormancy might be the “lesser evil” compared to treacherous apoptosis.

Neutralizing GDF-15 in muscle-invasive bladder cancer (MIBC): A neoadjuvant immunotherapy trial of visugromab (CTL-002) in combination with the anti-PD1 antibody nivolumab (GDFather-Neo).

TPS712 Background: Neoadjuvant chemotherapy (NACT) is a well-established treatment modality in MIBC but suffers from limited activity and significant toxicity. Neoadjuvant immunotherapy (I/O) demonstrated clinical safety and efficacy in various solid tumors including MIBC, with potentially less toxicity. Results from previous studies of single-agent I/O indicated a proportion of pathologic complete responses (ypT0N0) similar to that reported with NACT. Therefore, improving ypT0N0 responses remains a major task for treatment of MIBC. Increasing evidence emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical local immunosuppressive role. Apart from blocking immune-cell entry into tissues GDF-15 also has major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block I/O therapy success. Various translational research efforts indicated that GDF-15 may play a significant role for immunosuppression and T-cell exclusion in urothelial carcinoma (UC). Visugromab (CTL-002) is a GDF-15 neutralizing IgG4 monoclonal antibody that demonstrated in Phase 1 a favorable safety profile and promising clinical activity with durable and deep responses in PD-1/PD-L1 relapsed/refractory metastatic solid tumors in combination with the anti-PD1 antibody Nivolumab (Nivo)*. The Neo-GDFather trial is intended to investigate the combination of Visugromab with Nivo vs. Nivo monotherapy as neoadjuvant therapy for MIBC in patients (pts) who are ineligible for or elect not to undergo NACT. Primary endpoints are the complete pathologic response rate and radiologic response. Methods: Multi-center, parallel-cohorts and single-blinded Phase 2 study of neoadjuvant therapy in pts planned for radical cystectomy (RC). A total number of 30 subjects with stage T2-T4N0M0 MIBC will be enrolled and assigned 1:1 to receive either Nivo + Visugromab or Nivo + Placebo after stratification for CPS PD-L1 expression and cT-stage. Other inclusion criteria comprise an ECOG performance status 0-1 and a pure/predominant UC histology. No statistical assumptions were undertaken at this stage.Treatment consists of three 4-week cycles [i.v., Q4Wk], and RC is planned 4-8 weeks after last dose of study drug. After RC, pts will follow standard recommendations of EAU guidelines. Primary endpoints are the proportion of ypT0N0 response and radiologic response rate. Secondary endpoints comprise additional efficacy parameter, surgical and medical safety, PK and PD assessments. Translational research includes evaluation of immunologic parameters in the tumor, other immune-correlates and molecular profiles, as well as evaluation of treatment-emergent cytokine and chemokine profiles in peripheral blood. * Melero et al., #2501 ASCO Annual Meeting 2023 Oral Abstract Session. Clinical trial information: Not yet available.

Does Use of Intratumoral Injections in Solid Tumor Malignancies Improve Outcomes and Reduce Adverse Events? An Integrative Review.

The purpose of this review is to assess the efficacy and adverse events associated with intratumoral injection in the treatment of solid tumor malignancies. A literature review was conducted using PubMed, the Cochrane Database of Systematic Reviews, CINAHL, and Scopus databases from 2009 to 2022. A total of 588 articles were retrieved, with five selected based on inclusion and exclusion criteria. Inclusion criteria specified English language publications, in human trials, and use of intratumoral anticancer agents. The findings from this integrative review demonstrate treatment efficacy as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria with increased stable disease and partial response in patients as well as a prolonged survival period. Additionally, findings show that this therapy is associated with predominantly mild adverse events.

Incidence of immunotherapy-related hyperprogressive disease (HPD) across HPD definitions and cancer types in observational studies: A systematic review and meta-analysis.

While evidence of hyperprogressive disease (HPD) continues to grow, the lack of a consensual definition obscures a proper characterization of HPD incidence. We examined how HPD incidence varies by the tumor type or the type of definition used. We searched PubMed, Embase, the Cochrane Library of Systematic Reviews, and Web of Science from database inception to June 21, 2022. Observational studies reporting HPD incidence, in patients diagnosed with solid malignant tumors and treated with immune checkpoint inhibitors (ICI), were included. Random-effects meta-analyses were performed, and all statistical tests were 2-sided. HPD incidence was 12.4% (95% CI 10.2%-15.0%) with evidence of heterogeneity (Q = 119.32, p < 0.001). Meta-regression showed that the risk of developing HPD was higher in patients with advanced gastric cancer (adjusted odds ratio [OR], 10.83; 95% CI, 2.14-54.65; p < 0.001), hepatocellular carcinoma (adjusted OR, 7.99; 95% CI, 1.68-38.13; p = 0.006), non-small cell lung cancer (adjusted OR, 7.14; 95% CI, 1.58-32.29; p = 0.005), and mixed or other types (adjusted OR, 5.09; 95% CI, 1.12-23.14, p = 0.018) than in patients with renal cell carcinoma. Across definitions, HPD defined as a tumor growth kinetics ratio ≥ 2 (adjusted OR, 1.82; 95% CI, 1.08-3.07; p = 0.025) based on the Response Evaluation Criteria in Solid Tumors (RECIST) reported higher incidence than when HPD was defined as RECIST-defined progressive disease and a change in the tumor growth rate (TGR) exceeding 50% (∆TGR > 50). The incidence of immunotherapy-related HPD may vary across tumor types and definitions used, supporting the argument for a uniform and improved method of HPD evaluation for informed clinical decision-making.

Trop-2: A promising new therapeutic target in penile squamous cell carcinoma.

12 Background: Penile squamous cell carcinoma (PSCC) is an infrequent yet progressively prevalent malignancy. Despite ongoing advancements in personalized and immunotherapeutic approaches, patients grappling with the diagnosis of locally advanced or metastasized PSCC still confront a limited therapeutic arsenal, leading to an unfavorable prognosis. Consequently, an imperative mandate arises to explore alternative therapeutic modalities, particularly antibody-drug-conjugates (ADCs), which have demonstrated significant clinical efficacy in the context of metastatic solid tumor pathologies. Our aim was to ascertain the potential utility of ADCs targeting Trop-2 in both localized PSCC (PRIM) and patient-matched distant metastases (MET). Methods: Immunohistochemical analysis of Trop-2 expression was conducted in PRIM ( N=40) and their corresponding METs ( N=9, including lymph node and lung metastases). We assessed overall survival (OS) by stratifying patients into subgroups based on Trop-2 expression: weak (H-score 15-99) versus moderate/strong (H-score 100-300). Additionally, we explored the relationship between Trop-2 and HPV-dependency. Furthermore, Trop-2 mRNA expression levels were quantified via qRT-PCR, and an enzyme-linked immunosorbent assay was employed to measure Trop-2 in serum samples derived from PRIM ( N=40) and a healthy control group ( N=10). Results: We found a statistically significant increase in Trop-2 mRNA expression levels in individuals afflicted with PSCC compared to healthy controls ( p&lt;0.0001). Moreover, a notable elevation in Trop-2 protein expression was observed in the serum specimens obtained from PSCC patients ( p&lt;0.01). The majority of patients exhibited moderate to strong Trop-2 expression, indicative of a robust median H-score of 280 (interquartile range: 210-300). Subgroup analysis revealed a correlation between Trop-2 expression and HPV status ( p&lt;0.01), demonstrating discernible associations with more favorable clinical outcomes, as evidenced by the log-rank (Mantel-Cox) test ( p&lt;0.05). Conclusions: Trop-2 protein expression in PSCC holds prognostic significance. Furthermore, the elevated Trop-2 levels in both PRIM and PSCC metastases suggest that the Trop-2-targeted ADC, Sacituzumab govitecan, may emerge as a promising novel therapeutic intervention for these patients.

A retrospective study on the efficacy and safety of Envafolimab, a PD-L1 inhibitor, in the treatment of advanced malignant solid tumors.

Envafolimab, a PD-L1 inhibitor, has demonstrated potential in treating advanced malignant solid tumors (AMST). To study its' efficacy and safety in AMST, our retrospective study recruited 64 patients with various AMST, and treated with Envafolimab (400mg every 3weeks). We divided the patients into two cohorts: Cohort 1 (25 patients) receiving Envafolimab as first-line therapy, and Cohort 2 (39 patients) receiving it as second-line or subsequent therapy. Our analysis focused on Envafolimab's efficacy and safety. Over a median follow-up of 7.1 months, Cohort I reported a Disease Control Rate (DCR) of 72.0% and an Objective response rate (ORR) of 12.0%, while Cohort II had a DCR of 51.3% and an ORR of 5.1%. Notably, patients with more than four treatment cycles showed higher DCR and longer Progression-Free Survival (PFS) than those with fewer cycles. Adverse events were observed in 68.8% of patients, with severe events (CTCAE grade 3/4) in 14.1%. Most adverse events were mild, leading to treatment discontinuation in only 3.1% of patients, with no life-threatening events reported. In summary, Envafolimab is a safe and effective treatment for AMST, in both initial and later therapy stages, particularly with extended treatment duration, meriting further clinical trials.

Crosstalk Between NK Cell Receptors and Tumor Membrane Hsp70-Derived Peptide: A Combined Computational and Experimental Study.

Natural killer (NK) cells are central components of the innate immunity system against cancers. Since tumor cells have evolved a series of mechanisms to escape from NK cells, developing methods for increasing the NK cell antitumor activity is of utmost importance. It is previously shown that an ex vivo stimulation of patient-derived NK cells with interleukin (IL)-2 and Hsp70-derived peptide TKD (TKDNNLLGRFELSG, aa450-461) results in a significant upregulation of activating receptors including CD94 and CD69 which triggers exhausted NK cells to target and kill malignant solid tumors expressing membrane Hsp70 (mHsp70). Considering that TKD binding to an activating receptor is the initial step in the cytolytic signaling cascade of NK cells, herein this interaction is studied by molecular docking and molecular dynamics simulation computational modeling. The in silico results showed a crucial role of the heterodimeric receptor CD94/NKG2A and CD94/NKG2C in the TKD interaction with NK cells. Antibody blocking and CRISPR/Cas9-mediated knockout studies verified the key function of CD94 in the TKD stimulation and activation of NK cells which is characterized by an increased cytotoxic capacity against mHsp70 positive tumor cells via enhanced production and release of lytic granules and pro-inflammatory cytokines.

Biomimetic bright optotheranostics for metastasis monitoring and multimodal image-guided breast cancer therapeutics

Nanoparticle formulations blending optical imaging contrast agents and therapeutics have been a cornerstone of preclinical theranostic applications. However, nanoparticle-based theranostics clinical translation faces challenges on reproducibility, brightness, photostability, biocompatibility, and selective tumor targeting and penetration. In this study, we integrate multimodal imaging and therapeutics within cancer cell-derived nanovesicles, leading to biomimetic bright optotheranostics for monitoring cancer metastasis. Upon NIR light irradiation, the engineered optotheranostics enables deep visualization and precise localization of metastatic lung, liver, and solid breast tumors along with solid tumor ablation. Metastatic cell-derived nanovesicles (∼80 ± 5 nm) are engineered to encapsulate imaging (emissive organic dye and gold nanoparticles) and therapeutic agents (anticancer drug doxorubicin and photothermally active organic indocyanine green dye). Systemic administration of biomimetic bright optotheranostic nanoparticles shows escape from mononuclear phagocytic clearance with (i) rapid tumor accumulation (3 h) and retention (up to 168 h), (ii) real-time monitoring of metastatic lung, liver, and solid breast tumors and (iii) 3-fold image-guided solid tumor reduction. These findings are supported by an improvement of X-ray, fluorescence, and photoacoustic signals while demonstrating a tumor reduction (201 mm3) in comparison with single therapies that includes chemotherapy (134 mm3), photodynamic therapy (72 mm3), and photothermal therapy (88mm3). The proposed innovative platform opens new avenues to improve cancer diagnosis and treatment outcomes by allowing the monitorization of cancer metastasis, allowing the precise cancer imaging, and delivering synergistic therapeutic agents at the solid tumor site.

Repotrectinib: First Approval.

Repotrectinib (AUGTYRO™) is a next-generation, oral, small-molecule kinase inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. It is being developed by Turning Point Therapeutics, a wholly owned subsidiary of Bristol-Myers Squibb (BMS), for the treatment of locally advanced or metastatic solid tumours, including non-small cell lung cancer (NSCLC). Repotrectinib is a next-generation tyrosine kinase inhibitor rationally designed to inhibit ROS1 and TRK fusion, including in the presence of resistance mutations such as solvent-front mutations. In November 2023, repotrectinib received its first approval in the USA for the treatment of adults with locally advanced or metastatic ROS1-positive NSCLC. Repotrectinib is under regulatory review in China and the EU for NSCLC. Clinical studies of repotrectinib are ongoing in several countries in patients with NSCLC and other solid tumours (including primary central nervous system cancer) across both adult and paediatric patient populations. In addition, preclinical investigation of repotrectinib in multiple myeloma is underway in the USA. This article summarizes the milestones in the development of repotrectinib leading to this first approval for the treatment of locally advanced or metastatic ROS1-positive NSCLC.

BRAF - a tumour-agnostic drug target with lineage-specific dependencies.

In June 2022, the FDA granted Accelerated Approval to the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib for the treatment of adult and paediatric patients (≥6 years of age) with unresectable or metastatic BRAFV600E-mutant solid tumours, except for BRAFV600E-mutant colorectal cancers. The histology-agnostic approval of dabrafenib plus trametinib marks the culmination of two decades of research into the landscape of BRAF mutations in human cancers, the biochemical mechanisms underlying BRAF-mediated tumorigenesis, and the clinical development of selective RAF and MEK inhibitors. Although the majority of patients with BRAFV600E-mutant tumours derive clinical benefit from BRAF inhibitor-based combinations, resistance to treatment develops in most. In this Review, we describe the biochemical basis for oncogenic BRAF-induced activation of MAPK signalling and pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. We also discuss novel RAF inhibitors and drug combinations designed to delay the emergence of treatment resistance and/or expand the population of patients with BRAF-mutant cancers who benefit from molecularly targeted therapies.

Brachytherapy at the nanoscale with protein functionalized and intrinsically radiolabeled [169Yb]Yb2O3 nanoseeds.

Classical brachytherapy of solid malignant tumors is an invasive procedure which often results in an uneven dose distribution, while requiring surgical removal of sealed radioactive seed sources after a certain period of time. To circumvent these issues, we report the synthesis of intrinsically radiolabeled and gum Arabic glycoprotein functionalized [169Yb]Yb2O3 nanoseeds as a novel nanoscale brachytherapy agent, which could directly be administered via intratumoral injection for tumor therapy. 169Yb (T½ = 32days) was produced by neutron irradiation of enriched (15.2% in 168Yb) Yb2O3 target in a nuclear reactor, radiochemically converted to [169Yb]YbCl3 and used for nanoparticle (NP) synthesis. Intrinsically radiolabeled NP were synthesized by controlled hydrolysis of Yb3+ ions in gum Arabic glycoprotein medium. In vivo SPECT/CT imaging, autoradiography, and biodistribution studies were performed after intratumoral injection of radiolabeled NP in B16F10 tumor bearing C57BL/6 mice. Systematic tumor regression studies and histopathological analyses were performed to demonstrate therapeutic efficacy in the same mice model. The nanoformulation was a clear solution having high colloidal and radiochemical stability. Uniform distribution and retention of the radiolabeled nanoformulation in the tumor mass were observed via SPECT/CT imaging and autoradiography studies. In a tumor regression study, tumor growth was significantly arrested with different doses of radiolabeled NP compared to the control and the best treatment effect was observed with ~ 27.8MBq dose. In histopathological analysis, loss of mitotic cells was apparent in tumor tissue of treated groups, whereas no significant damage in kidney, lungs, and liver tissue morphology was observed. These results hold promise for nanoscale brachytherapy to become a clinically practical treatment modality for unresectable solid cancers.

Pulmonary metastatectomy in pediatric cancer patients at National Cancer Institute, Egypt: prognostic factors and outcome

BackgroundMetastatic tumors account for 80% of all lung tumors in children. Wilms tumour and osteosarcoma are the most tumors of childhood that produce lung metastases. The aim of the current study is to assess the prognostic factors of pulmonary metastatectomy in pediatric solid tumours as age, number, size, site,laterality, resectability of pulmonary nodules, and number of Thoracotomies. Calculate overall survival among patients who underwent pulmonary metastatectomy.MethodsIt is a retrospective study including all pediatric patients with metastatic solid tumors to lungs treated at pediatric oncology department, National Cancer Institute, Cairo University from 2008 to 2014. Fifty-five patients were included, 43 (78.2℅) patients of them had Osteosarcoma.ResultsThirty (54.5℅)patients were male. The mean age was 15 years ranging from (4.5- 23) years. The site of primary disease was at lower limbs in 43 (78.2%) patients. All patients underwent complete surgical resection of the primary disease with negative margin, 22(51.1%) of the osteosarcoma patients did amputation with tumor necrosis less than 90%. All patients received chemotherapy and only 9 received radiation therapy. The patients were classified into four groups according to time of diagnosis of pulmonary metastasis: at time of diagnosis in 13 (21.8%) patients, within treatment in 16 (30.9%) patients, within first year follow up in 18 (32.7%) patients and detected late in 8 (14.5%) patients. Bilateral lung metastasis diagnosed by CT chest were detected in 42 (76.4%) patients. Size of metastatic nodules was ranging from (0.5 to 10 cm) with mean 3.4 cm. Number of metastatic nodules was ranging from (1 to 28) median 4.Metastatic complications were detected in 19 patients. 5-year OS was 74.8% in the study group, and 68% in osteosarcoma patients. Effect of prognostic factors as sex, time of respectability, laterality, tumor necrosis of the 1ry disease, Timing of lung metastasis, size and site of the primary, Surgical approach of metastatectomy, postoperative complications on overall survival of the studied patients was done with significant P-value of tumor necrosis of the 1ry disease and Timing of lung metastasis 0.017, 0.001 respectively.ConclusionResection of pulmonary metastases of pediatric solid tumours is a safe and effective treatment that offers better survival.

Oncolytic virus CF33-hNIS monotherapy for the treatment of gastrointestinal (GI) malignancies.

749 Background: CF33-hNIS is a novel chimeric DNA vaccinia virus engineered with the human sodium-iodide symporter (hNIS) gene. CF33-hNIS selectively replicates in tumor cells leading to cell lysis and the release of tumor- and virus-associated antigens stimulating antitumor immunity. Here, we report results of patients with GI malignancies enrolled on a first-in-human phase 1 ascending, multiple dose, safety and tolerability study of CF33-hNIS, administered intratumorally (IT) or intravenously (IV) in adult patients with metastatic or advanced solid tumors (MAST). Methods: The MAST study is evaluating the safety of CF33-hNIS administered IT or IV, alone or in combination with pembrolizumab in patients with advanced or metastatic solid tumors with ≥ 2 prior lines of therapy (NCT05346484). CF33-hNIS is administered in 21-day cycles on C1D1 and C1D8, then D1 of each cycle thereafter. Pembrolizumab begins C2D1 for the combination groups and is administered Q3W. The co-primary endpoints are safety and to identify the recommended phase 2 dose. Secondary endpoints include objective response rate according to RECIST v1.1 and iRECIST, and to assess levels of viral replication via Single-Photon Emission Computerized Tomography (SPECT) with technetium-99. Results: As of Aug 2023, we report early results from seven patients with GI malignancies who received CF33-hNIS alone, including: colorectal cancer (3), bile duct (2), pancreatic (1) and hepatocellular carcinoma (1). The disease control rate is 86%. Notably one patient with cholangiocarcinoma, treated IT with 3.0x107 PFU, presented with pseudoprogression with a 49% increase in tumor burden after two cycles of therapy. By the 4th cycle they achieved a complete response (CR) with no known recurrence. A second patient with bile duct cancer, who previously progressed on checkpoint blockade therapy, achieved stable disease for &gt;5 months upon receiving IV-administered CF33-hNIS (3.0x107 PFU). Treatment-related adverse events for the CR patient included grade 1 fever and injection site reaction. All other patients experienced no treatment-related adverse events. SPECT analysis of the CR patient reveals intense levels of viral replication within the injected lesion and a concomitant increase in Th1 cytokines in cycle three that coordinated with tumor reduction. In-depth immunological changes in peripheral blood and on-treatment tumor biopsies will be presented. Conclusions: CF33-hNIS can replicate within cholangiocarcinoma lesions, as shown by SPECT imaging, and drive immunological changes known to promote antitumor immunity. CF33-hNIS monotherapy may be an effective and safe treatment option for GI malignancies, including cholangiocarcinoma, a rare disease with an unmet medical need. Treatment with CF33-hNIS monotherapy was well tolerated and the study has advanced to examine combination therapy with pembrolizumab. Clinical trial information: NCT05346484 .

A phase I study of EO-3021 in adult patients with solid tumors likely to express CLDN18.2.

TPS429 Background: Claudin 18 isoform 2 (CLDN18.2) belongs to a family of tight junction proteins with broad expression in gastric and gastroesophageal junction (GEJ), pancreatic, esophageal, and other solid tumors. Expression of CLDN18.2 in normal tissue is limited to the gastric mucosa, making it a promising antibody-drug conjugate (ADC) therapeutic target. Currently, there are no approved therapies targeting CLDN18.2. EO-3021 (also known as SYSA1801) is an ADC comprised of a fully human CLDN18.2 monoclonal antibody (mAb) specifically conjugated at glutamine 295 with a cleavable linker and MMAE with a homogenous drug-to-antibody ratio (DAR) of 2. In preclinical models, EO-3021 selectively delivers a potent cytotoxic MMAE payload directly to cancer cells expressing CLDN18.2, retains antibody-dependent cellular toxicity (ADCC) and complement-dependent cytotoxicity (CDC) activity, and exhibits a bystander effect.1 In an ongoing Phase 1 study in China (NCT05009966), EO-3021 exhibited signs of anti-tumor activity in patients with gastric cancer and had an acceptable safety profile.2 Outside of Greater China, EO-3021 is being evaluated by Elevation Oncology for the treatment of patients with advanced or metastatic solid tumors likely to express CLDN18.2, particularly gastric and GEJ adenocarcinomas. Methods: This is a Phase I, open-label, multi-center, dose escalation and expansion study to investigate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of EO-3021 in patients with solid tumors likely to express CLDN18.2 (NCT05980416). Patients whose tumors have progressed on or after standard therapy, or who are intolerable for available standard therapy are eligible for participation. Approximately 120 patients will be enrolled in this study. There are 4 planned dose levels in the dose finding portion of the study. Patients will receive EO-3021 intravenously (IV) once every three weeks until disease progression or unacceptable toxicity. The expansion cohort will evaluate EO-3021 in patients with gastric/GEJ adenocarcinoma. Provision of tumor samples (archived and fresh biopsy) is required for study enrollment. CLDN18.2 expression in tumor tissue via will be assessed by retrospective evaluation via central immunohistochemistry assay; results will be explored for possible correlation with tumor response. Enrollment in the dose escalation portion of the study began in August 2023. 1. Dan M, et al. Cancer Res. 83, 2023. 2. Wang Y, et al. J Clin Oncol. 41, 2023. Clinical trial information: NCT05980416 .

Colorectal cancer metastatic dMMR immuno-therapy (COMMIT) study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC)—NRG-GI004/SWOG-S1610.

TPS231 Background: Approximately 45% of dMMR/MSI-H mCRC in the immunotherapy arm progressed at 12 mos (KEYNOTE 177). We hypothesize that dMMR/MSI-H mCRC pts may be more effectively treated with the combination of PD-1/PD-L1 (PD-1) pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Preclinical work demonstrated synergistic effects between anti-PD-1/anti-VEGF as well as between oxaliplatin/anti-PD-1 in murine CRC models, and phase II data showed activity of anti-PD-1/anti-VEGF in chemotherapy refractory colon cancer. Upon AtezoTRIBE subgroup analysis of the 8 pts with dMMR mCRC treated with FOLFOXIRI+bev+atezo, median PFS was not reached, with the first patient having progression ~16 mos. Additionally, in other solid tumor malignancies, anti-PD-1 plus anti-VEGFr (i.e., HCC and RCC) as well as anti-PD-1 plus chemotherapy (i.e., gastroesophageal and lung cancers) combinations are standard first-line treatments. Methods: This two-arm prospective phase III open-label trial randomizes (1:1) mCRC dMMR/MSI-H to atezo monotherapy v mFOLFOX6/bev+atezo combination. Key inclusion criteria have been simplified on recent amendments to better mirror clinical practice for pts receiving mFOLFOX6/bev+/-atezo: One cycle of FOLFOX or CAPOX, with or without bev (or biosimilar) prior to enrollment allowed, dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; pts with total bilirubin ≤4.0 x ULN; duration of therapy for up to two years for both arms; imaging frequency on post-treatment follow up have been reduced; as has measurable disease per RECIST. The primary endpoint is PFS. Assuming the atezo monotherapy control arm has a 48% PFS at 24 mos as assessed by site investigator, we have 80% power to detect a hazard ratio of 0.6 (equivalent to 64.4% PFS at 24 mos) with alpha 0.025 one-sided. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Secondary endpoints include overall survival objective response rate, safety profile, disease control rate, and duration of response. Archived tumor tissue and blood samples will be collected for correlative studies. Harmonization of translational analyses is planned between GI004 (COMMIT) and A021502 (ATOMIC). The sample size has been modified with the accrual goal of 120 patients randomized between the two immunotherapy arms needed for study completion. Enrollment actively continues. Support: U10CA180868, -180822, -180888, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228 .

Phase 1/2 evaluation of revumenib in patients with advanced colorectal cancer and other solid tumors.

TPS227 Background: Aberrant transcription in cancer can be reversed by targeting critical epigenetic regulators. For example, in acute leukemias driven by increased HOX gene expression, inhibition of the menin-KMT2A interaction by revumenib induced remission in patients with heavily pretreated disease (Issa et al 2023). In solid tumors promoted by the aberrant activation of the Wnt/β-catenin pathway, in vitro data and in vivo studies have shown that small molecule inhibition of the menin-KMT2A interaction restricts growth, with potential therapeutic benefit in colorectal cancer (CRC), castration-resistant prostate cancer, estrogen receptor–positive breast cancer, gastrointestinal stromal tumors, and Ewing sarcoma. To test the therapeutic strategy of inhibiting the menin-KMT2A interaction in solid tumor malignancies, this study (NCT05731947) will evaluate revumenib in patients with CRC and other solid tumors. Revumenib is an oral, potent, selective inhibitor of the menin-KMT2A interaction. Methods: This phase 1/2 study is evaluating revumenib in adults aged ≥18 years with locally recurrent or metastatic CRC who have failed ≥1 prior line of therapy and in patients with other solid tumors who have failed available standard therapies. Inclusion criteria include diagnosis of microsatellite stable/proficient mismatch repair CRC or other solid tumors. Patients with CRC must be unable to receive or have disease that progressed on oxaliplatin, irinotecan, and bevacizumab; if left-sided RAS wild-type CRC, the patient must have received anti–epidermal growth factor receptor therapy. The primary phase 1 objectives are to determine the safety, tolerability, maximum tolerated dose, and recommended phase 2 dose of revumenib in patients with CRC and other solid tumors and to assess its antitumor effects. The phase 2 primary objective is to assess the antitumor effects of revumenib by blinded radiographic review. Phase 1 consists of all-comers’ dose escalation (phase 1a), and signal-seeking expansion in CRC (phase 1b). Using a rolling 6 design, the revumenib starting dose will be 163 mg 3 times daily in 28-day cycles. Up to 6 patients will be enrolled in a dose cohort. Dose escalation cohorts may be expanded and used for signal seeking in non-CRC tumor types. Phase 1b in CRC will begin when a potential phase 2 dose has been identified. The disease control rate at 6 cycles and overall response rate will be used to assess antitumor activity and will determine initiation of phase 2. In phase 2, patients with advanced CRC will be randomized 2:1 to revumenib or investigator's choice of 1 of 2 standard-of-care therapies. Patients will be followed for progression-free survival, with response assessments evaluated locally and confirmed by blinded radiographic review. As of September 5, 2023, 13 patients were enrolled in phase 1a of this study. Clinical trial information: NCT05731947 .

Cohort expansion from the phase 1 JEWEL-101 study investigating the tissue factor-targeting antibody-drug conjugate XB002 in patients with advanced solid tumors: Pancreatic and esophageal cancer cohorts.

TPS421 Background: Patients (pts) with metastatic pancreatic and esophageal cancers have poor prognosis, with 5-year survival rates of 3% and 6%, respectively (SEER 22). Tissue factor (TF), a factor VIIa receptor involved in initiation of the extrinsic coagulation cascade, is overexpressed in these tumors and has been associated with poor outcomes. XB002 is a novel antibody-drug conjugate (ADC) composed of a high-affinity TF-directed human monoclonal antibody conjugated to the linker-payload zovodotin. Zovodotin consists of an auristatin-based payload with a stable protease-cleavable linker; it is designed to have lower off-target payload deconjugation and improved tolerability versus other auristatin-based ADCs. In preclinical studies, XB002 showed encouraging safety and antitumor activity without affecting coagulation. JEWEL-101 (NCT04925284) is a phase 1, dose-escalation and multi-cohort expansion study evaluating XB002 alone and in combination with nivolumab or bevacizumab in pts with advanced solid tumors. Preliminary results from the dose-escalation stage showed XB002 was well tolerated at multiple dose levels, with low-grade ocular toxicity and no bleeding events or treatment-related peripheral neuropathy (PN).1 Presented here is the design of the expansion cohorts for pancreatic and esophageal cancers. Methods: Eligible pts must have an inoperable, locally advanced, metastatic, or recurrent solid tumor. Pts with pancreatic adenocarcinoma will receive XB002 single agent. Pts enrolled with esophageal squamous cell carcinoma (ESCC) will be randomized between 2 cohorts to receive either XB002 single agent or XB002 plus nivolumab. All pts in the pancreatic cancer and ESCC cohorts must have ECOG performance status of 0–1, measurable disease per RECIST v1.1, and have received 1–2 prior lines of systemic anticancer therapy, and radiographically progressed during or after their last therapy. Prior immunotherapy is allowed for pancreatic cancer and required for ESCC if locally considered standard of care and pts are eligible. Key exclusion criteria include prior treatment with TF-targeting or auristatin-based ADCs, and significant ocular disorders. Concomitant anticoagulants are permitted, and pts with PN are eligible, provided it is not impacting activities of daily living. The primary objective is objective response rate per RECIST v1.1 by investigator. Secondary objectives include safety, pharmacokinetics, immunogenicity, progression-free survival, duration of response, and overall survival. Enrollment is ongoing in the United States, Europe, and the Asia-Pacific region. 1. Ulahannan et al. ENA 2022. Clinical trial information: NCT04925284 .