Metastatic Solid Tumors Research Articles

Safety and preliminary efficacy of different doses of fecal microbiota capsule transplantation combined with anti-PD-1 inhibitor for patients with advanced malignant solid tumors.

e14622 Background: Chemotherapy combined with anti-PD-1 inhibitors has now become the standard first-line(1L) treatment for most malignant solid tumors. However, most Phase III studies have found that overall progression-free survival (PFS) with 1L combined subsequent immuno-maintenance therapy (IMT) is still less than 1 year. Fecal microbiota transplantation (FMT) has been shown to synergize with PD-1 antibodies to enhance efficacy. In this study, we administered oral microbiota capsule transplantation to patients(pts) during 1L IMT to evaluate its safety, preliminary efficacy, optimal dosage, and explore the changes in gut microbiota composition and serum metabolism (ChiCTR2100054928). Methods: This is a dose-escalation, exploratory clinical trial. The donor capsules were derived from the feces of a healthy 10-year-old child from a rural area. Twelve late-stage pan-cancer pts who had received standard 1L chemotherapy + PD-1 antibodies and achieved stable or responsive disease were enrolled. The first 3 patients were in the i group (5 capsules po tid d1-3). If no dose-limiting toxicities (DLTs) were observed, another 3 patients were escalated to the i+1 group (10 capsules po bid d1-3). If no DLTs were observed again, another 3 patients were escalated to the i+2 group (10capsules po tid d1-3), and so forth, until the i+3 dose group (20 capsules po bid d1-3). Simultaneously, patients continued receiving the original PD-1 IMT. Fecal samples were collected at baseline (S0), after 10 days (S1), 25days (S2), and 50days (S3) of FMT. Results: From March 2023 to December 2023, 12 pts were successfully enrolled. As of the data cutoff date (December 31, 2023), the median follow-up time was 9.05 months (6.5-9.5 months), and the median PFS has not been reached, with 3 patients experiencing disease progression. Four patients (33.3%) experienced Grade 1-2 FMT-related toxicities, including diarrhea, bloating, and abdominal pain, with no Grade 3 or higher adverse events observed. Fecal metagenomic sequencing analysis showed that the relative abundance levels of Blautia and Faecalibacterium significantly increased after FMT, peaking at day 25 and remaining higher than pre-transplant levels at day 50. We also found that patients in the i+1 group exhibited the greatest changes in microbial composition before and after transplantation, with high absolute and relative transplantation indices. Further analysis of host serum metabolism revealed an increase in molecules related to fatty acid metabolism, such as L-carnitine, stearic acid, and arachidic acid, especially a more pronounced increase in the i+1 group. Conclusions: This preliminary study demonstrates that the combination of oral microbiota capsule and immunotherapy can open up a more economical, safe, and effective avenue for 1L maintenance immunotherapy in tumors. Clinical trial information: ChiCTR2100054928.

A phase I clinical study to evaluate the safety, tolerability, immunogenicity, pharmacokinetics and preliminary efficacy of SCB-219M in patients with chemotherapy-induced thrombocytopenia (CIT): An interim analysis.

e15015 Background: CIT is a serious, chemotherapy-associated complication observed in a wide range of cancer patients with various types of cancer. Incidence of CIT can occur in about 15-25% of patients undergoing standard chemotherapy regiments with platinum, taxane and/or gemcitabine-based regimen. CIT can lead to chemotherapy dose delay or dose reduction, and potentially bleeding events. Currently, there is no FDA-approved therapy for CIT. SCB-219M, a thrombopoietin receptor agonist (TPO-RA) mimetic bispecific Fc-fusion protein produced from CHO cells can efficiently raise PLT count under normal and pathological conditions in laboratory animals. Methods: This is a single-arm, multi-center, open-label, dose escalation Phase Ia clinical study to evaluate the safety, tolerability, and immunogenicity, PK profile and preliminary efficacy of a single ascending dose of SCB-219M administered one day after a chemotherapy in prior CIT patients with malignant solid tumors and lymphoma. The study design of accelerated titration combined with "3 + 3" is used, and the number of subjects planned to enroll is 12 to be assigned to 4 cohorts with 2, 6, 10 and 15 mg/kg subcu administration of SCB-219M, respectively. Enrollment criteria include episode of CIT experienced (<75 × 109/L in PLT count) in prior cycle of chemotherapies and PLT count has recovered to >75 × 109/L prior to initiation of this study . The chemotherapy regimen allowed include either mono or combination chemotherapy (including targeted therapy and/or immunotherapy). The observation period of dose-limiting toxicities (DLTs) is 21 days. Chemotherapy is planned at each study site. There will be no change in the planned dose or frequency of chemotherapy in the study. Results: As of Dec 20, 2023, 9 prior CIT patients including 3 at 15 mg/kg were enrolled. SCB-219M was well tolerated. There were no SAEs or AESIs (Adverse Event of Special Interest) observed. DLT was not reached. A favorable PK profile, in particular in serum availability (AUC) and half-life (T1/2) was obtained. All 9 prior CIT patients in the study maintained PLT counts >75 x 109/L from 1-week following chemotherapies with a single dose of SCB-219M, and durable responses experienced through at least 3 weeks. Conclusions: In this interim analysis, drug safety, PK profile and durable efficacy are expected to support SCB-219M dosing interval of ≥2-weeks or a single dosing regimen within a chemotherapy cycle. Accordingly, a Phase Ib trial evaluating repeated dosing of SCB-219M is planned to initiate in 2024. Clinical trial information: NCT05426369 .

An open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT-112 in human leukocyte antigen-C*08:02–positive adult patients with unresectable, advanced, and/or metastatic solid tumors that are positive for the KRAS G12D mutation.

TPS2677 Background: The landscape of cancer treatment is evolving with the emergence of innovative immunotherapies. Among these, T cell receptor-engineered T cell (TCR-T) therapy has shown promise for patients with solid tumor malignancies. Targeting driver mutations, such as KRAS, may offer novel therapeutic options for patients with limited treatment options. Oncogenic driver mutations in KRAS typically involve single-base mutations at genomic hotspot locations. The KRAS isoform is mutated in 84% of RAS-driven cancers and in nearly 100% of pancreatic ductal adenocarcinoma (PDAC). The KRAS G12D mutation is the most frequent mutation in PDAC (28%), followed by colorectal cancers (12%). Despite its well-established target role in tumorigenesis, there is no FDA-approved therapy targeting the G12D variant. NT-112 is an autologous TCR-T cell therapy targeting the KRAS G12D mutation presented by HLA-C*08:02, armored by disruption of the gene encoding the transforming growth factor beta receptor type 2 (TGFBR2) in order to reduce the immunosuppressive effect of TGF-β in the tumor microenvironment. Methods: This first-in-human, open label, multicenter, Phase 1, dose escalation study aims to assess the safety, identify the MTD and evaluate potential anti-tumor activities of NT-112 in subjects with solid tumors. The study will enroll up to 24 adult subjects harboring the KRAS G12D mutation that are HLA-C*08:02 positive, who exhibit progressive or recurrent disease after at least one line of standard of care treatment. Enrolled patients will undergo leukapheresis, from which, CD4 and CD8 T cells will be enriched and activated ex vivo. The genes encoding the TGFBR2 and the endogenous TCR α and β chains are knocked out from the activated T cells utilizing clustered regularly interspaced short palindromic repeats (CRISPR-Cas9). The HLA-C*08:02-restricted TCR specific to the KRAS G12D mutation is knocked-in in the TCR α locus. Subjects will undergo standard lymphodepletion followed by a single infusion of NT-112 and concurrent, daily, subcutaneous, recombinant IL-2 for up to 8 days. Dose escalation will occur across 3 ascending dose levels following the BOIN design. Subjects will be monitored for dose-limiting toxicities for 28 days following NT-112 infusion. Disease response will be assessed according to the RECIST v1.1 criteria. Comprehensive translational analysis will be conducted to gain insights into the mechanism of action, biomarkers associated with treatment response, and potential mechanisms of resistance. All subjects will be followed for up to 15 years. Clinical trial information: NCT06218914 .

A first-in-human study of IK-595, an oral MEK/RAF molecular glue, in patients with RAS- or RAF-altered advanced solid tumors.

TPS3185 Background: Alterations in the RAS/RAF/MEK/ERK pathway are the most common drivers of oncogenesis. MEK is a clinically validated cancer target and despite FDA approval of several MEK inhibitors, their clinical utility has been limited to BRAF V600 mutant cancers and NF1 mutant neurofibromas mostly due to early emergence of resistance and low therapeutic indices. IK-595, a potent novel MEK-RAF molecular glue, is being developed to overcome these limitations. IK-595 traps MEK in an inactive complex with all RAF isoforms and blocks RAF-dependent MEK phosphorylation, thereby alleviating CRAF-mediated MEK reactivation that hinders the efficacy of approved MEK inhibitors in RAS/RAF-driven tumors, in addition to kinase independent CRAF activity. IK-595 exhibits potent single agent activity in a wide range of in vivo cancer models harboring various RAS/RAF alterations, including, but not limited to, lung, pancreatic, colorectal cancer (CRC), melanoma, and AML. The preclinical pharmacokinetic profile of IK-595 also enables flexible dosing schedules resulting in a broader therapeutic window. Methods: This is a phase 1, first-in-human, open-label, multicenter study to evaluate IK-595 as monotherapy in patients with RAS- or RAF-altered advanced solid tumors for whom there are no other further treatment options known to confer clinical benefit. Dose escalation uses a Bayesian Optimal Interval Design (BOIN) in patients with advanced and unresectable, or metastatic solid tumors with confirmed RAS/RAF gene alterations. Backfilling of cleared dose levels with key target indications will initiate upon achievement of efficacious plasma exposures. Dose expansion will occur in genetically defined cohorts, for example NRAS-mutant CRC and malignant melanoma, as well as BRAF non-V600 and KRAS mutant tumors using a Simon 2-stage adaptive design. IK-595 will initially be administered on an intermittent dosing schedule in 30-day cycles. Additional dosing schedules may be explored. Primary objectives of the study are to evaluate safety and tolerability of IK-595 and to determine the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD). Secondary objectives include evaluation of preliminary antitumor activity by RECIST 1.1, pharmacokinetic (PK) parameters, and pharmacodynamic effects of IK-595 on pERK in paired tumor biopsies. Key exploratory endpoints include changes in pERK in peripheral blood cells, changes in pERK target genes in tumor biopsies, and assessment of candidate baseline response biomarkers. The study began in December 2023 and enrollment in Cohort 1 was completed with no DLTs; dose escalation continues to enroll. Clinical trial information: NCT.

Exploring the safety and efficacy of GT201 as a first-in-class autologous tumor-infiltrating lymphocyte monotherapy in advanced solid tumors.

2547 Background: GT201, featuring a membrane bound IL-15 stably expressed on tumor-infiltrating lymphocytes (TIL), aims to augment TIL persistence and function as well as ameliorate immune suppression within the tumor microenvironment, offering potential for durable responses in advanced solid tumor patients. We present data from 7 patients enrolled in an open-label, single-arm, multicenter clinical study (NCT05729399), investigating the safety profile and efficiency trend of GT201 therapy. Methods: The GT201 phase 1 trial is designed with the primary endpoint of DLT evaluation and the secondary endpoint of measuring preliminary efficacy parameters including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR, and overall survival (OS) following the RECIST v1.1. Results: As of January 22, 2024, a cohort of 7 pts has been enrolled in the study, with a median age of 48 and a median of 3 prior lines of therapy. Among these patients, 1 pt has a history of bone metastases, 2 pts have a history of liver metastases, and 1 pt has a history of brain metastases. Following the standard FC lymphodepletion, pts underwent infusion with GT201 at doses ≥ 5x109 total viable cells. Five pts subsequently received IL-2 as part of the treatment protocol. Treatment-related AEs were observed in ≥ 50% of pts with no grade≥3 AEs. Grade ≥ 3 AEs related to FC lymphodepleting chemotherapy and IL-2 included decreased lymphocyte count, decreased neutrophil count, and decreased white blood cell count, pyrexia and increased heart rate. Notably, all grade ≥3 AEs were either recovered or downgraded to grade ≤ 2 within 14 days. Among the 7 response-evaluable patients across various indications, including Non-Small-Cell-Lung Cancer (NSCLC), melanoma malignant, cervical cancer, and ovarian cancer, 3 patients (42.9%) achieved a confirmed partial response (PR), and 2 patients (28.6%) demonstrated stable disease (SD) as their best response. Notably, among the NSCLC subgroup, disease control (SD ≥ 24 weeks or any PR) was observed in all 3 pts (3/3, 100 %). GT201 cells can be detected in all patients receiving treatment, indicated by both staining IL15RA protein on peripheral T cells and measuring the transgene copy number in peripheral white blood cells. GT201 cells expanded robustly in patients and persist in peripheral blood beyond at least 6 months post cell infusion. Conclusions: In patients with heavily pretreated advanced or metastatic solid tumor, GT201, when infused after FC lymphodepletion and followed by high dose IL-2, exhibits a manageable safety profile. Notably, GT201 has demonstrated a favorable clinical profile in NSCLC, with an encouraging objective response rate, response durability, and no GT201-treatment related grade≥3 AEs. Clinical trial information: NCT05729399 .

Preliminary results of phase I/II study to evaluate safety and efficacy of combination pucotenlimab with epidermal growth factor receptor-ADC (EGFR-ADC) MRG003 in patients with EGFR positive solid tumors.

6013 Background: Pucotenlimab (HX008) is a recombinant humanized PD-1 inhibitor approved for marketing in China, and MRG003 is an EGFR-ADC which has shown promising anti-tumor activity in squamous cell carcinoma of the head and neck (SCCHN) and nasopharyngeal carcinoma (NPC) in multiple clinical studies. In the preclinical studies, the combination of them has demonstrated a synergistic antitumor effect. This study was aimed to assess the safety and efficacy of the combination therapy in patients (pts) with locally advanced or metastatic solid tumors known to express EGFR. Methods: In this Phase I/II dose escalation and expansion study, eligible pts were treated with 3.0 mg/kg HX008 combined with MRG003 every 3 weeks, with an escalated dosing ranging from 1.5 mg/kg to 2.3 mg/kg. The primary endpoints were maximum tolerated dose (MTD), recommended Phase II dose (RP2D) of combination and objective response rate (ORR). Secondary endpoints included duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS). Results: As of 30 January 2024 (cut-off date), 33 pts (9 NPC, 1 SCCHN and 3 other solid tumors pts in Phase I, 14 NPC and 6 SCCHN pts in Phase II) were enrolled in this study with a median age of 52 (31,65), and 25 pts (76%) were male. 11 (33%) pts were ECOG PS 0. The most commonly reported treatment-related adverse events (TRAEs) included pruritus (46%), rash (33%), AST increased (30%), anemia (30%). Grade 3-4 TRAEs occurred in 4 pts (12%), and mainly was white blood cell count decreased (9%) and hypokalemia (6%). The only DLT event occurred in the 2.3mg/kg dose group, and the RP2D of MRG003 determined was 2.0mg/kg by SMC. Out of the 27 evaluable pts, 17 pts achieved PR and 7 pts achieved SD, thus the ORR and DCR were 63.0% (95%CI: 42.4, 80.6) and 88.9% (95%CI: 70.8, 97.7), respectively. In the Phase II, among 9 evaluable EGFR-positive NPC pts progression after first-line treatment of PD-1 plus platinum-based chemotherapy, 2 CR, 5 PR and 2 SD were observed, ORR and DCR were 77.8% (95%CI:40.0, 97.2) and 100% (95%CI:66.4, 100), respectively. Five evaluable systemic treatment naïve SCCHN pts with EGFR-positive, 3 PR and 1 SD were observed, ORR and DCR were 60% (95%CI:14.7, 94.7) and 80% (95%CI:28.4, 99.5), respectively. The DOR and PFS in the study were immature. The longest patient treated has had a DOR for more than 17 months and still ongoing. Conclusions: The Phase I/II study pts treated with HX008 in combination with MRG003 demonstrated good tolerability and encouraging antitumor activity in NPC and SCCHN, especially in PD-1 treatment failed NPC pts. The Phase II study is currently ongoing. Research Sponsor: Shanghai Miracogen Inc. Clinical trial information: NCT05688605.

Impact of carboplatin and cisplatin shortages on treatment patterns in patients with metastatic solid tumors.

11149 Background: The United States experienced cisplatin (CP) and carboplatin (CB) shortages in 2023, leading to potential rationing or switching to alternative therapies in multiple cancers. Using a US nationwide, real-world oncology dataset, we assessed changes in the use of CP and CB in 7 cancers during the shortage period. Methods: All patients (pts) from the Flatiron Health electronic health record-derived de-identified database (~280 cancer clinics, ~800 sites of care) with a machine learning-extracted metastatic (met) diagnosis of a cancer of interest between March 2022 and June 2023 and evidence of first-line (1L) therapy, were selected. Pts with multiple primaries were excluded. Platinum of interest was identified based on frequency of pre-period 1L use for a given cancer. The pre-period was June 2022 through first month of reported shortage (February 2023 for CP; April 2023 for CB); data cutoff was June 2023. Clinical characteristics of platinum-treated pts stratified by pre- vs post-period by disease were assessed. 1L platinum utilization rates (UR), calculated as the proportion of 1L-treated pts initiating CB/CP within 30 days of met diagnosis, were plotted by month. Cohort-level impact was evaluated with an interrupted time series analysis—overall and stratified by practice type, practice size, and socioeconomic status (SES). Multiple testing was controlled using the Benjamini-Hochberg procedure. Results: 10,983 pts received 1L therapy in the study period. Monthly platinum UR were stable across diseases in the pre-period. However, there was a significant post-period decrease in CB usage for non-small cell lung (NSCLC) and endometrial cancers (EC), and a decreasing trend in UR for CB in bladder (BC), ovarian (OC), and small cell lung cancers (SCLC). We also observed a decreasing trend in CP usage for cholangiocarcinoma (CC). Post-period monthly UR were stable for CB and CP in head and neck cancer (HNC), and for CP in BC. Odds ratios (OR) representing the month-over-month change in the odds of receiving platinum therapy during both pre- and post-periods are shown (table). OR trends varied by practice type and disease; no notable trends were seen by practice size or SES. UR with additional follow-up times will be presented. Conclusions: We observed decreased platinum use across multiple cancers during the shortage period, most notably for met NSCLC and EC, suggesting shortages led oncologists to seek alternatives to standard 1L platinum-based regimens. Further study of how treatment changes due to platinum shortages impacted pt outcomes is warranted. [Table: see text]

Phase 1 study of GT101 as an autologous tumor infiltrating lymphocyte (TIL) therapy in advanced solid tumors.

2548 Background: Adoptive cell therapy utilizing autologous TIL has demonstrated efficacy and durable long-term responses in patients with certain advanced solid tumors progressed after conventional therapies. We present data from 14 patients enrolled in the study of GT101, a Phase 1, open-label, single-arm, multicenter trial (NCT05430373) of autologous TIL therapy, aiming to investigate the safety profile, efficiency trend and the duration of response. Methods: The trial was designed with the primary endpoint on evaluating DLT and characterizing the safety profile of GT101 in solid tumor patients measured by the incidence of Grade ≥ 3 treatment-emergent adverse events (TEAEs). The secondary endpoints were to assess efficacy parameters including overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS) according to RECIST v1.1. Results: As of November 10, 2023, a cohort of 14 patients received treatment with a median age of 46.9 and a median of 2.6 lines of prior therapies. Following a standard FC-based lymphodepletion, patients underwent GT101 infusion at doses ≥ 5x109 cells with median dose of 3.7x1010 cells, followed by high-dose IL-2 administration. Most of observed Grade ≥ 3 AEs were related to the FC conditioning regimen and IL-2, including decreased lymphocyte count, decreased white blood cell count, decreased neutrophil count, anemia, pyrexia and decreased platelet count. The majority of these AEs were recovered within 14 days, while a few were downgraded to ≤ Grade 2 within 4 weeks. Among 14 enrolled patients across various indications (small-cell-lung cancer, melanoma, cervical cancer), the ORR was 35.7%. Specifically, 4 pts (28.6%) had a confirmed partial response (PR), 1 pt (7.1 %) achieved complete response (CR), and 8 pts (57.1 %) had stable disease (SD) as their best response. One pt had unconfirmed disease progression (PD). Notably, among 11/14 patients with cervical cancer, the ORR was 45.5% (5/11) with 4 pts (36.4%) achieving PR and 1 pt (9.1 %) achieving CR. Disease control was observed in 10/11 pts (90.9%), and the median PFS was 4.2 months for this cohort. The CR patient underwent a long-term follow-up and the duration of CR and PFS (estimated by Kaplan-Meier) was 24 weeks and 36 weeks, respectively. Post GT101 infusion, T cell expanded robustly in the peripheral blood of all patients with median Tmax 6.83 days and average 15.9 days. Conclusions: In the GT101 Phase 1 study, no treatment-related SAEs and DLT were observed. In patients with heavily pretreated advanced or metastatic solid tumors, GT101 exhibited a manageable safety profile under the treatment protocol of lymphodepletion and high-dose IL-2 and a favorable clinical profile, particularly in cervical cancer, with an encouraging ORR and sustained response duration. Clinical trial information: NCT05430373 .

Open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT-175 in human leukocyte antigen-a*02:01-positive adult subjects with unresectable, advanced and/or metastatic solid tumors that are positive for the TP53 R175H mutation.

e14514 Background: The TP53 tumor suppressor gene is the most commonly mutated gene across all cancer types, and TP53 R175H is the most common recurrent mutation across indications, identified in 6.7% of patients with breast cancer, 6% of patients withs colorectal cancer, and 4.2% of patients with pancreatic cancer. No therapy is approved for treatment directly targeting TP53 R175H. NT-175 is an armored autologous T-cell product expressing an HLA-A*02:01-restricted TCR recognizing TP53 R175H with disruption of the endogenous TCR and the transforming growth factor beta receptor type 2 (TGFBR2) genes. Methods: This first-in-human phase I, open label study will assess the safety and preliminary anti-tumor activity, identify the maximum tolerated dose (MTD), and evaluate the persistence, and functional capacity of NT-175 in subjects with advanced, recurrent unresectable/metastatic solid tumors refractory to treatment options. The study will enroll approximately 24 subjects harboring TP53 R175H and HLA-A*02:01. Enrolled patients will undergo leukapheresis from which CD4 and CD8 T cells will be enriched and activated ex vivo. The endogenous TCR α and β chain gene are knocked out utilizing clustered Regularly Interspaced Short Palindromic repeats (CRISPR-Cas9) and the TCR encoding an HLA-A*02:01-restricted TCR specific to the TP53 R175H mutation is inserted in the TCR α locus. Additionally, the T cells are edited to disrupt the gene encoding the TGFBR2 to reduce the immunosuppressive effect of TGF-β in the tumor microenvironment. Subjects will undergo lymphodepletion chemotherapy with fludarabine and cyclophosphamide followed by a single infusion of NT-175 and subcutaneous recombinant IL-2 administration for up to 8 days. Dose escalation will occur across 3 ascending dose levels following the BOIN design. Subjects will be monitored for dose-limiting toxicities for 28 days after NT-175 infusion. Tumor response will be assessed by RECISTv1.1 criteria. All subjects will be followed for up to 15 years. Primary endpoints include safety, dose limited toxicities, MTD determination, and recommended Phase II dose. Secondary endpoints include preliminary efficacy measures. Translational analysis will evaluate potential biomarkers for insights into mechanism of action, response prediction, or resistance mechanisms. The study was activated in March 2023 and is open to accrual; 5 patients have been enrolled as of 4 Jan 2024.

A phase 1/1b study of the IL-2 prodrug WTX-124 in patients with locally advanced or metastatic solid tumors after checkpoint inhibitor therapy: Initial results of the combination dose escalation with pembrolizumab.

2623 Background: High dose IL-2 can produce durable remissions in patients who have progressed on checkpoint inhibitors but is infrequently used due to its life-threatening toxicities such as vascular leak syndrome (VLS). WTX-124 is a half-life extended, masked cytokine (INDUKINE molecule) rationally engineered to release wild type IL-2 in tumors. We previously reported that WTX-124 is clinically active as a monotherapy at doses safely administered in the outpatient setting. Here we update the data and present initial results from the combination dose escalation with pembrolizumab (anti-PD-1; NCT05479812). Methods: In this first-in-human trial, WTX-124 is administered IV Q2W alone or with pembrolizumab 400 mg IV Q6W. Eligible patients are adults with relapsed/refractory solid tumors who have previously received standard of care checkpoint inhibitor regimens. Primary endpoints are safety and ORR; secondary endpoints are PK, PD, immunogenicity, and PFS/OS. The dose escalation is guided by a mTPI-2 study design. Results: As of January 29, 2024, 32 patients have been treated with WTX-124 in five monotherapy dose escalation cohorts (1-18 mg; N=24) and two combination cohorts (3-6 mg; N=8). The most common AEs related to WTX-124 monotherapy were arthralgias, myalgias, fatigue and pruritis. Of ten evaluable patients treated with 12 or 18 mg WTX-124 monotherapy, three had objective responses, including a confirmed CR in a patient with cutaneous squamous cell cancer and unconfirmed PRs in patients with melanoma and gastroesophageal junction cancer. On-treatment tumor biopsies showed evidence of increased lymphocyte activation and PD-L1 expression. Addition of pembrolizumab to 3-6mg WTX-124 did not change the character of AEs observed with WTX-124 monotherapy. Related AEs occurred more frequently for the combination than for 3-6mg WTX-124 monotherapy, but all were mild to moderate in severity (Gr1: 74.2%, Gr2: 25.8%) and there was no increase in the percentage of Gr2 events. No DLTs, related serious AEs, treatment discontinuations due to related toxicities, or occurrences of VLS have been observed in any patient treated to date with either WTX-124 or WTX-124/pembrolizumab. Pembrolizumab did not affect WTX-124 or IL-2 PK. WTX-124 has been escalated to 12 mg IV Q2W, the initial monotherapy dose that produced objective responses, in combination with pembrolizumab. Conclusions: WTX-124 administered as a monotherapy IV Q2W in the outpatient setting is well tolerated and clinically active in patients with relapsed/refractory solid tumors after checkpoint inhibitor therapy. Preliminary results from the ongoing combination dose escalation with pembrolizumab show no new safety signals. Updated data on safety, biomarkers, and preliminary clinical activity for the combination will be presented. Clinical trial information: NCT05479812 .

Dose escalation of KY-0118, PD-1, and IL-2v due-target fusion protein in patients with advanced renal clear cell carcinoma, urothelial carcinoma, and malignant melanoma.

e14505 Background: KY-0118 is an anti-PD1 and IL-2v(variant) fusion protein for advanced solid tumors. The non-α biased design reduces the binding to IL2-Raβγ and enhanced binding to PD-1 & IL2-Rβγ positive TILs to drive increased proliferation and activation of NK and CD8+ T cells without unwanted expansion of Tregs. KY-0118 adopts specific single design, only 67kDa MW thus obtains excellent tumor penetration activity. The preclinical data shows higher antitumor activity in several CDX models compared with nivolumab and IL2wt. KY-0118 monotherapy is currently in Phase I escalation. Methods: The phase I dose escalation is a traditional 3+3 design, KY-0118 on Days 1, 8 and 15, 21-day treatment cycle, 9 dose levels (0.3μg/kg-64μg/kg) or higher doses of 3 to 6 patients are planned. The dose expansion cohort is currently enrolling. The primary endpoint was to evaluate the safety, tolerability, and determine the DLT, MTD, RP2D of KY 0118 when given alone. Secondary objectives are PK/PD characteristics and preliminary evidence of efficacy via ORR per RECIST v1.1 and iRECIST. Results: Up to Jan 31, 2024, 21 patients have been treated, the median number of prior lines of systemic therapy was 2. The dose level 8 (48µg/kg) of DLT observation period is ongoing, no DLT was observed in the administered dose groups. Most of TEAEs are transient grade 1-2, no TEAE led to withdrawal from this study. The most common nonhematologic TRAEs were pyrexia, flu-like symptoms, nausea, fatigue. 2 patients had grade 3 hematologic toxicity. Treatment-related sAEs were observed in one patient (include nausea, vomiting, and pulmonary embolism, now recovered and continuing treatment). No patients experienced complete or partial response, but several showed evidence of antitumor activity, at the dose of 36 ug/kg, 21% shrinkage of target lesions in a patient with RCC, the DCR for the 12, 24, and 36μg/kg dose levels are 33%, 75%, and 67%, respectively. Conclusions: These preliminary data suggest that KY-0118 demonstrated a manageable safety profile and encouraging early evidence of activity has been observed in locally advanced and/or metastatic solid tumors. Enrollment is ongoing, further results are forthcoming. Pts: 21; AEs: 399; TEAEs: 289 (100%); AESI: 13; sAEs: 8. Clinical trial information: NCT06175780 .

A multi-center, open-label phase 1/1b dose finding, safety, and pharmacokinetic study of MBRC-101, an Anth-EphA5 monomethyl auristatin (MMAE) antibody drug conjugate, in advanced refractory solid tumors.

TPS3161 Background: EphA5 receptor is a member of the Ephrin receptor tyrosine kinase family. Several lines of compelling nonclinical evidence indicate EphA5 is a novel and selective target for solid tumor-directed therapy. Expressed only minimally in normal tissues, it is highly expressed in non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma (HNSCC), and breast, colorectal, pancreatic, gastric, and hepatic malignancies. MBRC-101 is a novel antibody drug conjugate (ADC) composed of an anti-EphA5 antibody conjugated to an MMAE payload (drug-to-antibody ratio of 4) through a valine citrulline cleavable linker. In pre-clinical toxicology studies and testing against a variety of cell-derived (CDX) and patient-derived (PDX) xenograft solid tumor models expressing EphA5--including NSCLC, triple negative breast cancer (TNBC), and HNSCC--MBRC-101 demonstrated favorable safety profiles and robust anti-tumor activity. Methods: This first-in-human, Phase 1/1b, multicenter, open-label study is examining the safety and efficacy of MBRC-101 in patients with advanced metastatic solid tumors refractory to standard treatment. Phase 1 will identify potential optimal biologically relevant doses (OBRD) and the maximum tolerated dose (MTD) of MBRC-101 at one or more dosing regimens. Phase 1b will evaluate the safety and preliminary clinical activity of MBRC-101 at potential OBRDs. Phase 1 will enroll patients (n ≈ 30) with advanced or metastatic solid tumors. EphA5 expression will not be required for enrollment into Phase 1 but will be assessed retrospectively. A modified toxicity probability interval (mTPI-2) method will guide dose escalation using a pre-specified decision matrix. The primary endpoints are MTD, dose limiting toxicities (DLTs), treatment emergent adverse events (TEAEs), and clinical laboratory tests. Phase 1b (n ≈ 60 patients) will include 3 expansion cohorts (n ≈ 20 patients per cohort): Cohort A, NSCLC; Cohort B, triple negative or HR+/HER2- breast cancer; and Cohort C, solid tumors irrespective of histologic tissue type (i.e., tumor agnostic) excluding NSCLC and breast cancer. Expression of EphA5 in primary or metastatic tumor tissue will not be required for enrollment into cohorts A and B but will be required for Cohort C. The primary endpoints are TEAEs, clinical laboratory tests, and investigator-assessed objective response rate (ORR) by RECIST v1.1 and clinical evaluation. Secondary endpoints for Ph1 and 1b include PK analytes and EphA5 expression as determined by immunohistochemistry (IHC). A Safety Review Committee will monitor safety at each dose escalation in Phase 1 and at regular intervals throughout Phase 1b. Clinical trial information: NCT06014658 .

PRIMROSE: A modular phase 1/2a study of AZD3470, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP deficient advanced solid tumors.

TPS3179 Background: Protein arginine methyltransferase 5 (PRMT5) is an epigenetic enzyme that catalyzes symmetric dimethylation of arginine substrates, regulating multiple cell processes. Deletion of the methylthioadenosine phosphorylase gene MTAP in tumor cells results in accumulation of the metabolite methylthioadenosine (MTA), a partial inhibitor of PRMT5, potentially rendering tumor cells susceptible to further PRMT5 targeting. Clinical activity of first-generation, non-selective PRMT5 inhibitors (PRMT5i) is limited by bone marrow toxicity due to lack of selectivity between normal cells and MTAP-deficient tumor cells. Second-generation PRMT5i, including AZD3470, should selectively target MTAP-deficient tumor cells whilst sparing normal cells. AZD3470 preferentially binds PRMT5 in the presence of MTA in MTAP-deficient tumor cells, inhibiting PRMT5 methylation activity, and is less effective in MTAP-proficient cells. PRIMROSE (NCT06130553) is a first-in-human, Phase 1/2a, open-label, multicenter study of AZD3470 as monotherapy and in combination with anti-cancer agents in patients with MTAP-deficient advanced / metastatic solid tumors. Methods: Eligible patients are aged ≥18 years with MTAP-deficient advanced or refractory solid tumors, ≥1 prior line of treatment in the recurrent / metastatic setting, ≥1 measurable lesion per RECIST v1.1, ECOG performance status 0/1, adequate organ and bone marrow function, and no prior treatment with PRMT5i. Module 1 will evaluate AZD3470 monotherapy. Part A (dose escalation) will enroll up to ~54 patients and follow a modified toxicity probability interval-2 (mTPI-2) design with once-daily dosing in 21-day cycles. Treatment will be given until progression or discontinuation criteria are met. Part B (dose optimization and expansion) will expand specific patient populations and / or tumor types, with up to ~30 patients per cohort; dosing will be based on safety and tolerability data from Part A. Further modules for combination treatments may be added based on emerging supportive data. The primary objectives are to assess safety and tolerability, including dose-limiting toxicities, and to determine the recommended phase 2 dose of AZD3470. The secondary objective is evaluation of efficacy, including objective response rate, duration of response, disease control rate, change in tumor size, progression-free survival, and overall survival. An additional secondary objective in Module 1 is to assess pharmacokinetics. The study is planned to take place in ~20 centers across eight countries. The study was opened to enrollment in December 2023. Clinical trial information: NCT06130553 .

Hematologic parameters as predictors of overall survival in metastatic solid tumor and aggressive lymphoma.

e23053 Background: Aggressive cancer is associated with an increased rate of thrombosis. In addition to body mass index (BMI), the Khorana score has identified several hematologic parameters associated with an increased risk of thrombosis. In this study, we assessed the relationship of these parameters with overall survival. Methods: Using data from our tumor registry, we selected patients with aggressive lymphomas (AL), glioblastoma multiforme (GBM), metastatic prostate (MP), metastatic lung (ML), and metastatic colorectal (MCRC) cancer from 2018 to 2023. Laboratory data were extracted from our electronic medical record, with a timeframe of 90 days before and 30 days after first contact, but prior to initiating treatment. We analyzed the relationship of hemoglobin (Hgb), white blood cell (WBC) count, platelet (Plt) count, and body mass index (BMI), with overall survival (OS). Each cancer type was analyzed as a separate group and multivariable analysis was controlled by sex and age at diagnosis. Dichotomizing the variables from categories of the Khorana score, we evaluated the relationship of such variables and OS using Kaplan-Meier Analysis and Cox Proportional Hazards Models. Patients were censored at two years of follow-up. Data analysis was done using R (version 4.3). Results: Of 2,362 patients, 55% were male, and median age was 63 years. (Cancer types: 622 ML, 604 AL, 453 GBM, 281 MCRC, 203 MP, and 199 MB). An initial, pre-treatment Hgb < 10 g/dL was associated with a shorter OS in patients with ML, MCRC, MP, and AL patients. Plt ≥350 x 109/L was associated with a shorter OS in ML and MCRC patients. WBC > 11 x 109/L was associated with a shorter OS in ML, AL, and MCRC, and a BMI ≥35 was associated with a shorter OS only in GBM patients (Table). Conclusions: While not in all cancer types, the hematologic parameters of the Khorana score that predict thrombosis correlate with a reduced overall survival. This effect was significant for different parameters in different cancers. The increased hazard ratio is beyond that which would be expected from thrombosis-related mortality. Our study is limited to data from our single institution and the retrospective nature of the study. [Table: see text]

Improving ethnic and racial diversity in biomarker-driven clinical trials: A proof of concept with the BASECAMP-1 master prescreening study of patients with high-risk solid tumors with human leukocyte antigen-A*02 (HLA-A*02) loss of heterozygosity (LOH).

1604 Background: Diversity in clinical studies is essential to address health disparities, but racial and ethnic minorities are often underrepresented in clinical studies, especially in precision medicine studies using genetic data (1). BASECAMP-1 (NCT04981119) is an ongoing prescreening study to identify patients with unresectable advanced or metastatic solid tumors and tumor-associated HLA-A*02 LOH for the EVEREST-1 and -2 Tmod chimeric antigen receptor T-cell therapy trials. When enrollment began in 2021, eligibility for Part 1 was restricted to patients with germline HLA-A*02:01 based on preclinical data. Additional analysis revealed the blocker in the Tmod construct had activity across HLA-A*02 subtypes (Mock, et al. Mol Ther Oncolytics.2022). Eligibility for Part 1 was then expanded to all HLA-A*02 subtypes, allowing enrollment of more diverse patient populations. HLA-A*02 allele subtypes vary by ethnicity and race; the frequency of HLA-A*02:01 is 96% in non-Hispanic Whites, but ranges from 53% to 73% in other ethnicities and races. The frequency of all other HLA-A*02 allele subtypes (HLA-A*02:XX) is <5% in non-Hispanic Whites but up to 66% in other ethnicities and races (2,3). Methods: Patients eligible for BASECAMP-1 were identified at United States study sites. All patients screened before January 16, 2024, for Part 1 were included for demographic and central lab HLA-A typing. The % increase in eligibility and % of heterozygous HLA-A*02 patients with HLA-A*02:XX were calculated by ethnicity and race. Results: A total of 1124 patients were screened for germline HLA-A*02 typing; 431 patients were HLA-A*02:01 heterozygous, of whom 37 (9%) were Hispanic, 14 (3%) African American (AA), 2 (<1%) American Indian or Alaska Native, 17 (4%) Asian or Pacific Islander (API), and 324 (75%) non-Hispanic White (Table). The eligibility expansion identified 62 patients with HLA-A*02:XX heterozygosity, of whom 6 (10%) were Hispanic, 6 (10%) AA, 19 (31%) API, and 25 (40%) non-Hispanic White. Conclusions: By expanding enrollment to include HLA-A*02:XX, 16% more Hispanic, 43% more AA, and 112% more API patients were identified, improving the diversity in this trial compared with that of initial enrollment. 1. Aldrighetti, et al. JAMA Netw Open 2021. 2. Ellis, et al. Human Immunol. 2000. 3. Gragert, et al. Human Immunol.2013. Clinical trial information: NCT04981119 . [Table: see text]

Phase 1/2 trial of the HPK1 inhibitor NDI-101150 as monotherapy and in combination with pembrolizumab: Clinical update.

3083 Background: NDI-101150 is a potent, selective, oral inhibitor of hematopoietic progenitor kinase 1 (HPK1), with a different immunotherapy mechanism to other checkpoint inhibitors. NDI-101150 reactivates anti-tumor activity of T-cells, B-cells and dendritic cells (DCs), even under immunosuppressive conditions. Methods: Safety and preliminary efficacy (primary endpoints) of NDI-101150 alone (50–200 mg once-daily in 28-day cycles) and in combination with pembrolizumab are being assessed in patients (pts) with relapsed or metastatic solid tumors. NDI-101150 monotherapy expansion cohorts in renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC) and gastric/gastroesophageal (G/GEJ) cancer are also being assessed. Results: Dose escalation/expansion data as of Dec 13, 2023 are presented. Treatment (tx)-related adverse effects (TRAEs) in the safety set (N=39) for NDI-101150 monotherapy are presented in the table. 30 (76.9%) pts reported ≥1 TRAE and 5 (12.8%) pts reported grade ≥3 TRAEs. Most common TRAEs were nausea, vomiting, diarrhea and fatigue. Combination tx TRAEs (N=7) recapitulate the monotherapy profile (data not shown). NDI-101150 induced clinical benefit in 4/24 (16.7%) response-evaluable pts: complete response in 1 pt with clear cell RCC; stable disease (SD) ≥6 months in 3 pts (RCC [21 months], pancreatic cancer and endometrial cancer). Unconfirmed SD was noted in 2 pts with RCC, and in 1 pt each with NSCLC and G/GEJ cancer. Nearly dose-proportional increases in exposure were observed on Day 1 of Cycle 1 (C1) across 50–200 mg, with steady state achieved between Days 15 and 28 of tx. Pharmacokinetic profiles of monotherapy and combination tx cohorts were similar. Sustained inhibition of pSLP76 of >50% relative to pre-tx levels (predicted to achieve efficacy in nonclinical models) was observed at all doses tested by Day 15 of C1. Using a custom 12-plex immunofluorescence assay to monitor changes in the tumor immune microenvironment, an on-tx biopsy assessment from a pt with RCC showed increased infiltration of activated CD8+ T-cells and DCs compared to archival biopsy, aligning with the proposed mechanism of action. Conclusions: The observed clinical benefit and safety profile support continued evaluation of NDI-101150 as a viable next-generation immunotherapeutic. Clinical trial information: NCT05128487 . [Table: see text]

An open-label phase I study to evaluate the safety, tolerability and preliminary efficacy of YY001 in patients with advanced solid tumors.

e15104 Background: Prostaglandin E2 (PGE2) receptor 4 (EP4) is the master regulator of immunosuppressive myeloid cells (IMCs), one of the major drivers of resistance to immune checkpoint blockade therapy. YY001, a novel and selective EP4 antagonist, effectively blocked the function of IMCs and enhanced cytotoxic T-cell mediated tumor elimination in preclinical studies. Here we report the preliminary data of YY001 in Chinese patients with advanced solid tumors from a phase I study approaching completion. Methods: The key eligibility criteria include: patients aged 18 to 75 years with histologically or pathologically confirmed advanced or metastatic solid tumors; refractory to or intolerant of standard treatment; at least one measurable lesion per RECIST v1.1; ECOG PS 0-1. Accelerated titration and classic 3+3 design were applied for dose escalation. The first dose was administrated once orally within 1 hour after a meal. After 3-days observation, patients took YY001 QD orally continuously in each 21-day treatment cycle. Results: 16 eligible patients were enrolled, including 100mg (n = 1)、200mg (n = 1)、300mg (n = 4)、400mg (n = 3)、500mg (n = 7), and no dose limiting toxicity (DLT) occurred. All patients have received multiple prior treatments before enrolling and the median number of prior treatment lines was five. As of the cut-off date (December 18, 2023), the median of treatment duration is 44 days and the longest is 194 days. No treatment-related adverse events (TRAEs) of ≥ Grade 3 were reported. The most common TRAEs were gastrointestinal disorders, alanine aminotransferase increased, fibrin D-dimer increased, alkaline phosphatase increased and hypoalbuminemia. No patients have DLT or AE leading death. 14 patients were evaluated and 2 patients withdrew from the study before tumor assessment. 6 of 14 patients (42.9%) achieved stable disease and 1 patient achieved Non-CR/Non-PD. The disease control rate was 46.2% (95% Cl 19.2, 74.9). The median progression-free survival and median overall survival were 2.38 (95% Cl 1.93, 4.00) and 10.12 (95% Cl 4.01, -) months, respectively. By the cut-off date, 11 patients were still alive, 1 patient was lost to follow-up and 1 patient is still under treatment. PK analysis concluded YY001 exposure increased in human plasma with increasing dose gradients from 100mg to 300mg. From 300mg to 500mg, the drug exposure in human plasma remained essentially the same, suggesting the PK value peak has been reached. The recommended phase II dose would be 300mg to 500mg. In addition, a median t1/2 of 8.7h was derived from 100mg to 500mg dose groups. Conclusions: The preliminary results suggest that YY001 had a manageable safety/tolerability profile and promising efficacy in patients with advanced solid tumors. YY001 will be combined with immune checkpoint inhibitor in a phase II study subsequently. Clinical trial information: NCT06228846 .

EXPRESS study: A trial exploring the association of low level of genomic alteration with exceptional and unexpected response to targeted therapies in patients with advanced solid tumors.

e15140 Background: Small subsets of pts treated with targeted therapies (TT) present exceptional and unexpected response (1-10%), which could be driven and correlated by a low level of genomic alterations in genes identified as causally implicated in cancer. Conversely, the multiplication of the genomic alterations in such genes would decrease the oncogenic de-addiction process. Methods: EXPRESS is an exploratory, multicenter, prospective trial conducted in pts with locally advanced or metastatic solid tumors, who presented an exceptional and unexpected response to an antineoplastic TT. This research aimed to explore whether tumors with a low level genomic alteration (mutation, amplification, deletion) as assessed by whole exome sequencing (WES) are associated with exceptional and unexpected response. Secondary endpoints including the identification of novel candidate somatic molecular profiles and host immunologic characteristics susceptible to drive exceptional and unexpected response will be reported later. Results: 439 pts were identified over 32 centres from December 2016 to April 2021. Out of 270 pts confirmed with an exceptional response by our review committee of cases, 183 were included in the EXPRESS study. Exceptional responder population is summarised (Table). Out of 183, WES analysis was performed for 103 pts (56.3%). Genomic analysis failure was predominant in the breast and lung cohort (60.9% and 52.5%). The number of genomic alterations in the EXPRESS cohort was lower than in the TCGA control cohort (median[Q1-Q3]: 11[7-17] vs 19 [11-32], p<0.001). A lower number of genomic alterations was also reported in the melanoma (8[5-13] vs 33[17-51], p<0.001) and lung cancer cohort (8[5-17] vs 22[13-34], p<0.001) but not in the breast and kidney cohorts (13[10-21] vs 17[10-29], p=0.41 and 12[9-14] vs 11[7-17], p=0.89). Conclusions: Compared to the TCGA cohort, a low level of genomic alteration is associated with exceptional response in pts with lung cancer and melanoma. A comparison with a matched population based on genomic criteria in the TCGA is undergoing and will be presented at the conference. Clinical trial information: NCT02701907 . [Table: see text]

Multi-specimen comprehensive genomic profiling for diagnostic disambiguation in advanced and metastatic solid tumors.

e15166 Background: Predictive biomarker testing for therapy selection is the primary intended use of tissue-based comprehensive genomic profiling (CGP) in advanced and metastatic cancer patients. This study aimed to characterize oncologists’ use of multi-specimen CGP to elucidate diagnostic uncertainty in the course of usual care for advanced and metastatic cancer patients. Methods: To assess the nature and extent to which CGP is potentially used for diagnostic disambiguation, we retrospectively identified patients tested at a reference laboratory with CGP at least twice (Illumina TruSight Oncology 500 assay), and the first two serial CGP tests for each patient were selected for study inclusion. We then explored patient demographics, rare ( < 20 cases per 100k individuals) vs common diagnoses, tested tissue characteristics, time between CGP orders, and differences in genomic variant profiles between test pairs to characterize potential diagnostic use cases. Results: In all, 337/15,717 (2.1%) of patients underwent multi-CGP (June 2021-December 2023). All CGP test pairs were performed using different tissue specimens from 2 separate surgical cases (80.7%) or 2 different blocks for the same surgical case (19.3%). Compared to single-CGP, patients with multi-CGP were younger on average (65 vs 68 years), more often female (54.6% vs 50.6%), and had a greater proportion of lung (45.7% v 39.8%), breast (10.7% vs 6.7%), and unknown primary (7.1% vs 5.2%) tumors. CGP test pairs were grouped for comparison by test order diagnoses submitted by oncologists as: (Group 1) 2 different primary tumors (16%); (Group 2) same primary tumor, different histologic subtypes (19%), or; (Group 3) same primary tumor, same histologic subtype (65%). In Group 1, multi-CGP was performed more frequently for patients with a rare diagnosis for at least 1 test compared to Groups 2 and 3 (81.5% vs 43.8% or 19.6%, p < 0.001), especially for cancers of unknown primary origin (31.5% vs 7.8% and 0.9%, p < 0.001). In Groups 1 and 2, testing for both a primary and a metastatic site was twice as common compared to Group 3 (43% and 41% vs 22%, p = 0.017). In Group 3, 80% of patients were represented by common tumor types, and were most often tested > 30 days apart (64.4%). The mean percent overlap in detected genomic variants was lowest for patients in Groups 1 and 2 where patients had 2 different primary diagnoses or 2 different histologies, and highest in Group 3, where patients had the same primary diagnosis and histology for both tests, (41.5%, 54.5%, 60%, p = 0.008). Conclusions: In practice, most multi-CGP testing is ordered serially for a subset of advanced cancer patients with common tumor types. Use of simultaneous multi-CGP for diagnostic decision-making appears to be limited to a fraction of patients representing more rare tumors with distinct diagnostic conundrums, warranting further exploration of clinical utility.

Navigating the Complexities of Brain Metastases Management.

The management of brain metastases, a potentially devastating complication of advanced cancers, has become increasingly complex with advancements in local and systemic therapies. Improved outcomes and extended survival for patients with metastatic solid tumors have led to a surge in the prevalence and possibly incidence of brain metastases, affecting up to 40% of individuals with solid tumors. Enhanced imaging technologies contribute to more accurate and early detection, shaping the understanding of the intricate landscape of this condition. Traditionally, surgery and radiation stood as the mainstays of treatment because of the limited efficacy of systemic therapies within the brain. However, emerging clinical data, particularly in melanoma, lung, and breast cancers, reveal promising results with novel systemic treatments such as immunotherapy and targeted therapies. Despite the historical exclusion of patients with active brain metastases from clinical trials, a shift is occurring toward a more inclusive approach. This chapter delves into the multifaceted challenges associated with managing brain metastases, with a focus on the evolving landscape of systemic approaches as well as the intricacies of shared decision making, providing a comprehensive overview of the current state and future directions in navigating the complexities of brain metastases management.