Combination Of Tyrosine Kinase Inhibitors Research Articles

Efficacy and safety of tyrosine kinase inhibitors with thoracic radiotherapy for patients with oncogene-mutated non-small cell lung cancer: a meta-analysis.

Tyrosine Kinase Inhibitors (TKIs) is an important therapy for patients with oncogene-mutated Non-Small Cell Lung Cancer (NSCLC). However, acquired resistance remains a major challenge. The efficacy of TKIs plus thoracic radiotherapy (RT) in oncogene-mutated NSCLC patients is uncertain. Therefore, we performed a meta-analysis to comprehensively evaluate the efficacy and safety of thoracic RT plus TKIs in oncogene-mutated NSCLC patients. The following databases were searched for relevant studies: PubMed, EMBASE, and Cochrane Library. Studies comparing the efficacy and safety of TKIs plus RT with TKIs alone in oncogene-mutated NSCLC patients were included in this analysis. Outcomes were median progression-free survival (mPFS), median overall survival (mOS), and incidence of adverse events (AEs). This analysis performed a subgroup analysis of the efficacy of first-line TKIs in combination with RT. This meta-analysis included 12 studies with 2936 patients (n = 823 patients with TKIs plus thoracic RT, n = 2113 patients with TKIs alone). The results showed that patients who received treatment with TKIs plus thoracic RT were associated with superior mPFS and mOS than those who were treated with TKIs alone (hazard ratio [HR]: 0.42, 95% CI 0.30-0.59, p < 0.00001; HR: 0.56, 95% CI 0.41-0.70, p < 0.00001, respectively). Subgroup analyses showed that TKIs plus thoracic RT as first-line treatment was associated with better mPFS and OS (HR: 0.37, 95% CI 0.26-0.52, p < 0.00001; HR: 0.47, 95% CI 0.31-0.70, p = 0.0002, respectively). Although the combination of TKIs with thoracic RT was associated with an increased risk of total AEs (odds ratio [OR]: 1.17, 95% CI 1.06-1.29, P = 0.002), there was no significant difference in serious AEs (grade ≥ 3) (OR: 1.06, 95% CI 0.58-1.92, P = 0.86). The most frequently occurring radiation-related AEs were radiation pneumonitis, radiation esophagitis, and radiation dermatitis, with overall rates of 41.3%, 15.4%, and 11.1%, respectively. The incidence of severe radiation pneumonitis and radiation esophagitis was 4.5% and 6.2%, respectively. In comparison to TKIs alone, TKIs plus thoracic RT are associated with survival benefits, especially as a first-line treatment option. Although TKIs plus thoracic RT may increase the risk of total AEs, it did not increase the risk of severe AEs. Therefore, TKIs plus thoracic RT may be a promising therapeutic regimen for oncogene-mutated NSCLC patients.

In-depth exploration of the focus issues of TKI combined with radiotherapy for EGFR-mutant lung adenocarcinoma patients with brain metastasis: a systematic analysis based on literature metrology, meta-analysis, and real-world observational data

BackgroundThere is a growing interest in utilizing a combination of brain radiotherapy (RT) and tyrosine kinase inhibitors (TKIs) for patients diagnosed with brain metastases (BM) in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma (LAC). The current status of this treatment strategy remains a subject of debate.MethodsWe initiated our study by conducting a comprehensive literature search using the SCI-expanded database of Web of Science Core Collection (WoSCC). We utilized the VOSPviewer software to analyze various aspects of the research, including the year of publication, authorship, keywords, and country.Subsequently, we performed an extensive and systematic literature search on popular online databases. Our primary outcome measures were overall survival (OS) and intracranial progression-free survival (iPFS), both quantified by hazard ratios (HRs).Additionally, for data verification, we included data from patients in non-small cell lung cancer with brain metastasis who underwent therapeutic intervention at the Cancer Prevention and Treatment Center of Sun Yat-sen University and the Radiotherapy Department of Hanzhong Central Hospital between August 2012 and November 2021.ResultsThe bibliometric analysis revealed an increasing trend in research focused on the combination of RT and TKIs for the management of lung cancer brain metastases over the previous decade. Then, nine studies consistent with the research direction were included for meta-analysis. The meta-analysis showed that the OS (HR = 0.81, 95% confidence interval: 0.69–0.94; P = 0.007) and iPFS (HR = 0.71, 95% confidence interval: 0.61–0.82; P < 0.001) of the combination therapy were significantly prolonged. Finally, 168 EGFR-mutated BM advanced LAC patients in the real world were verified, and the median iPFS of the combination therapy (n = 88 and EGFR-TKIs alone (n = 80) were 16.0 and 9.0 months, respectively, (P < 0.001). The median OS was 29.0 and 27.0 months, respectively, with no dramatic difference (P = 0.188).ConclusionsResearch on EGFR-mutant LAC brain metastasis has turned towards exploring optimal treatment strategies for this condition. Our meta-analysis and real-world data analysis consistently demonstrate that combination therapy offers a substantial improvement in patient survival compared to EGFR-TKI monotherapy. Notably, among patients undergoing salvage radiotherapy (RT), our subgroup analysis reveals that those initially treated with third-generation TKIs experience more significant benefits than those treated with first- or second-generation TKIs.

7959 Combination Therapy Of Multi-Targeted Tyrosine Kinase Inhibitors And Immune Checkpoint Inhibitors In Advanced Adrenocortical Carcinoma

Abstract Disclosure: F. Yaylaci Mert: None. V. Balderrama Brondani: None. L.P. Marcal: None. M. Campbell: None. C. Jimenez: None. J. Varghese: None. A. Shah: None. M.A. Habra: None. Background: Adrenocortical carcinoma (ACC) is a rare cancer with limited response to systemic chemotherapies. Monotherapy with multi-targeted tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitors (ICIs) in ACC patients has limited efficacy. Combining TKIs with ICIs increased response rates in other malignancies but the efficacy of this approach in ACC is still unknown. This retrospective study aims to evaluate the efficacy and safety of the combined use of TKIs and ICIs in patients with advanced ACC. Methods: A single-center, retrospective cohort study in patients with advanced ACC treated with the combination of TKIs and ICIs. Response rates, progression-free survival (PFS), overall survival (OS) calculated from the time of combination, disease control rate (DCR), and safety profile were the main study objectives. Results: Seventeen patients were treated with combination therapy of TKI (lenvatinib or cabozantinib) and ICI (pembrolizumab) between January 2017 and December 2023. Eleven patients were women, the median age was 43.4 years (range 21.9-66.6), and 8 (47.1%) patients presented cortisol-producing tumors. All patients had prior systemic therapy, median of 3 (range 1-9) lines of therapy. The median duration of TKI+ICI therapy was 7.1 months (range 0.7-69.7). The treatment was discontinued in one patient due to a grade 3 adverse event (gastrointestinal fistula) after 1.6 months of treatment. Best overall responses were as follows: partial response 2 (13%), stable disease 8 (53%), and progressive disease 5 (34%). DCR was 58.8%. Median PFS was 7.1 months (range 0.7-66.4). One death occurred during the study due to disease progression. The median OS was 21.3 months (range 3.3-70.3). At the time of this report, 7 patients (41%) were still alive. Conclusion: The combined use of TKIs and ICIs in heavily treated ACC patients is associated with occasional durable responses and has a predictable and manageable side effect profile. This combination is worthy of a prospective clinical trial to validate the findings and establish new lines of therapy for this rare disease. Presentation: 6/2/2024

First-line treatment of EGFR-mutated non-small cell lung cancer with brain metastases: a systematic review and meta-analysis

This systematic review and network meta-analysis evaluates first-line treatment options for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases. We analyzed 24 randomized controlled trials (RCTs) involving 2,682 patients, comparing various EGFR tyrosine kinase inhibitors (TKIs) and combination therapies. Direct comparisons showed that the addition of bevacizumab or chemotherapy to first-generation (1G) EGFR-TKIs improved overall survival (OS) compared to 1G TKIs alone, with HRs of 0.704 (95% CI: 0.433–0.973) and 0.682 (95% CI: 0.464–0.899), respectively. However, third-generation (3G) TKI monotherapy did not significantly improve OS compared with 1G TKIs, with an HR of 0.855 (95% CI: 0.511–1.198). Indirect comparisons suggested that the combination of 3G TKIs with chemotherapy provided the most significant improvements in OS and progression-free survival (PFS), significantly outperforming 3G TKIs, with HRs of OS 1.69 (95% CI: 1.14–3.4) and PFS 2.13 (95% CI: 1.28–3.54). Intracranial PFS was best with 1G TKIs plus bevacizumab. Our findings suggest that 3G EGFR-TKIs in combination with chemotherapy may be the most effective strategy for patients with EGFR-mutant NSCLC and brain metastases, though further head-to-head trials are needed for validation.

Cadonilimab (PD-1/CTLA-4) in combination with lenvatinib in unresectable hepatocellular carcinoma (uHCC): A retrospective real-world study

BackgroundPrevious research has shown that combining tyrosine kinase inhibitors (TKIs) with immunotherapy results in synergistic clinical efficacy. Cadonilimab, the first approved bi-specific antibody targeting PD-1 and CTLA-4, was studied to evaluate its efficacy and safety in combination with Lenvatinib as a first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC). MethodsA retrospective study was conducted on 29 uHCC patients diagnosed at Nanfang Hospital, Southern Medical University, between July 7, 2022, and March 3, 2023. Patients received Cadonilimab (10 mg/kg, IV, every 3 weeks) combined with Lenvatinib (8 mg, orally, daily). The primary endpoint was the objective response rate (ORR), with secondary endpoints including disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), median time to progression (mTTP), and safety. ResultsBy April 2023, 29 patients had been enrolled in the study. The ORR was 37.9 %, DCR was 82.8 %, mPFS was 8.1 months, mTTP was 8.2 months, and mOS was not reached. A total of 93.1 % of patients experienced at least one treatment-related adverse event (TRAE). The most common adverse events were weight loss (51.7 %), increased aspartate aminotransferase (48.3 %), leukocytopenia (48.3 %), and neutropenia (48.3 %). TRAEs of grade 3 or higher occurred in 51.7 % of patients, with no grade 4 TRAEs observed. ConclusionThis study demonstrated the efficacy and safety of this combination, potentially improving outcomes as a first-line therapy, and offering a novel therapeutic approach for advanced HCC.

Real-World Study of Systemic Treatment after First-Line Atezolizumab plus Bevacizumab for Hepatocellular Carcinoma in Asia-Pacific Countries

Introduction: Atezolizumab plus bevacizumab is a commonly used first-line regimen for advanced hepatocellular carcinoma (HCC) treatment owing to its superior outcomes compared to sorafenib. However, optimal subsequent treatment options for patients with HCC who progressed on first-line atezolizumab plus bevacizumab remain unclear. Methods: This multinational, multi-institutional, retrospective study included patients with HCC from 22 centers in five Asia-Pacific countries who were treated with first-line atezolizumab plus bevacizumab, which was discontinued for any reason. The endpoints included progression-free survival (PFS) and overall survival (OS) according to patient characteristics and second-line regimens. Results: Between June 2016 and May 2023, 1,141 patients were treated with first-line atezolizumab plus bevacizumab, of whom 629 (55.1%) received subsequent treatment. Sorafenib and lenvatinib were the most commonly administered second-line regimens (53.9% and 25.6%, respectively). Overall, the median PFS and OS were 2.9 and 8.0 months, respectively. Lenvatinib had longer PFS (4.0 vs. 2.3 months) and OS (8.0 vs. 6.3 months) than sorafenib. Patients treated with tyrosine kinase inhibitor (TKI) plus immune checkpoint inhibitor (ICI) (n = 50, 8.3%) showed PFS and OS of 5.4 and 12.6 months, respectively. Lower tumor burden and lenvatinib or TKI plus ICI use were associated with longer second-line PFS. Preserved liver function was associated with improved OS. Conclusions: In patients with HCC who progressed on first-line atezolizumab plus bevacizumab, sorafenib and lenvatinib were the most commonly used second-line regimens in Asia-Pacific countries, with lenvatinib resulting in longer OS than sorafenib. The second-line TKI plus ICI combination exhibited promising efficacy, suggesting the potential role of continuing ICIs beyond disease progression.

Development of a genome atlas for discriminating benign, preinvasive, and invasive lung nodules.

To tackle misdiagnosis in lung cancer screening with low-dose computed tomography (LDCT), we aimed to compile a genome atlas for differentiating benign, preinvasive, and invasive lung nodules and characterize their molecular pathogenesis. We collected 432 lung nodule tissue samples from Chinese patients, spanning benign, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA). We performed comprehensive sequencing, examining somatic variants, gene expressions, and methylation levels. Our findings uncovered EGFR and TP53 mutations as key drivers in - early lung cancer development, with EGFR mutation frequency increasing with disease progression. Both EGFR mutations and EGF/EGFR hypo-methylation activated the EGFR pathway, fueling cancer growth. Transcriptome analysis identified four lung nodule subtypes (G1-4) with distinct molecular features and immune cell infiltrations: EGFR-driven G1, EGFR/TP53 co-mutation G2, inflamed G3, stem-like G4. Estrogen/androgen response was associated with the EGFR pathway, proposing a new therapy combining tyrosine kinase inhibitors with antiestrogens. Preinvasive nodules exhibited stem cell pathway enrichment, potentially hindering invasion. Epigenetic regulation of various genes was essential for lung cancer initiation and development. This study provides insights into the molecular mechanism of neoplastic progression and identifies potential diagnostic biomarkers and therapeutic targets for lung cancer.

Efficacy and safety of HAIC combined with tyrosine kinase inhibitors versus HAIC monotherapy for advanced hepatocellular carcinoma: a multicenter propensity score matching analysis.

This study aimed to assess the clinical efficacy and safety of the combined approach involving hepatic arterial infusion chemotherapy (HAIC) and tyrosine kinase inhibitors (TKIs) for the treatment of advanced hepatocellular carcinoma (HCC). In this multicenter retrospective study conducted from January 2020 to December 2023, we reviewed advanced HCC patients who were treated either with HAIC alone or with a combination of HAIC and TKIs. To address initial disparities between the two groups, we employed propensity score matching (PSM). Tumor response evaluation was performed following RECIST 1.1 criteria. We compared survival outcomes, including overall survival (OS), progression-free survival (PFS), and objective response rate (ORR), between the two treatment groups. Safety assessments were conducted for all patients. Following the eligibility review, 138 patients underwent combined treatment with HAIC and TKIs (HT group), while 198 patients received HAIC monotherapy (HA group) and met the inclusion criteria for enrollment in this study. After PSM, 107 patients were assigned to each group. The HT group exhibited a longer median OS (18.0 versus 8.8 months; hazard ratio [HR], 0.52, p < 0.001) compared to the HA group. Median PFS was also longer in the HT group, although without statistical significance (6.0 versus 4.7 months; HR, 0.85, p = 0.265). The HT group demonstrated a higher ORR (41.1% versus 25.2%; p = 0.020). No significant differences were observed between the two groups in the incidence of all adverse events (AEs) or grade 3/4 AEs (any grade: 81.2% for HT versus 78.8% for HA, p = 0.68; grade 3/4: 18.1% for HT versus 13.6% for HA, p = 0.29). Importantly, all AEs were manageable and acceptable. Notably, no grade 5 AEs occurred in either group. Combination therapy involving HAIC and TKIs effectively prolonged survival in advanced HCC patients. It represented a preferable alternative to HAIC monotherapy, with manageable safety.

Immune effect and prognosis of transcatheter arterial chemoembolization and tyrosine kinase inhibitors therapy in patients with hepatocellular carcinoma.

The combination of transcatheter arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) has shown broad prospects in prolonging the survival of patients with hepatocellular carcinoma (HCC). TACE and TKIs can affect the immune microenvironment in patients with HCC. To determine the overall effects and differences between TACE and different TKIs combinations on the immune microenvironment. Data and immune cell profile test results from 213 HCC patients treated with TACE combined with apatinib, lenvatinib, sorafenib, or donafenib before and after 3 wk of treatment were collected. Monocytes were co-cultured with LM3 liver cancer cells, and their ability to inhibit cancer cell growth was analyzed using the MTT method and a nude mouse subcutaneous tumorigenesis experiment. Simulated combined therapy was done using an in situ liver cancer C57BL/6 male mouse model, and the immune response of tumor tissues was analyzed using immunohistochemistry. Compared to before combination therapy, the proportion of programmed cell death protein 1 (PD-1)+ mononuclear cells and the number of CD4+ T cells decreased in the TACE + apatinib group, while the number of absolute count of CD4+ and CD8+ T cells increased in the TACE + lenvatinib group. Furthermore, the number of regulatory cells decreased in the TACE + donafenib group, whereas the number of CD8+ T and natural killer cells increased. Additionally, monocytes in the TACE combined with donafenib or lenvatinib groups had a stronger ability to inhibit cancer cell growth than those in the other groups. Combining TACE with donafenib or lenvatinib increased CD8+ T cell infiltration into the tumor tissue. In addition, the proportion of PD-1+ in CD8+ cells, absolute CD8+ T lymphocyte count, and regulatory T cells proportion were independent prognostic factors affecting the survival time of patients with HCC. TACE, in combination with different TKIs, produces different immune responses. Specifically, TACE combined with donafenib or lenvatinib may induce strong anti-tumor immune responses.

A Quality by Design (QbD) driven gradient high performance liquid chromatography method development for the simultaneous estimation of dasatinib and nilotinib in lipid nanocarriers

Tyrosine kinase inhibitors (TKIs) are effective as a targeted treatment for chronic myeloid leukemia (CML), which can selectively suppress BCR-ABL1 kinase activity. CML therapy with TKIs combination has been supported by in-vitro, in-vivo, and patient-based data where the nilotinib-dasatinib co-administration has exerted superior anticancer efficacy with greater cellular uptake, less resistance to chemotherapy, and no additive adverse events encountered. Therefore, it is essential to develop a suitable analytical method for the simultaneous estimation of these drugs in the developed novel lipid nanocarriers like liposomes. Design of Experiment (DoE) has been implemented as a tool of QbD to systematically investigate the relation between the HPLC method attributes and analytical responses, i.e., chromatographic detection, quantification, and peak properties for dasatinib and nilotinib. An Ishikawa diagram is constructed to delineate possible influencing variables to the analytical performances. Afterward, 4 factors 2 level full factorial design (FFD) was employed to model and identify the main effects and interaction effects between the factors selected after the initial risk assessment. The suggested design space for optimized chromatographic conditions by QbD analysis is linear within the selected range of drug concentrations, accurate and precise, sensitive, and robust according to the ICH guidelines. The optimal method is comprised of a 1 mL/min flow rate of mobile phase (ACN and 20 mM KH2PO4 of pH 7.00) in gradient mode at 25 °C column temperature for 20 μL sample injection volume and detection wavelength fixed at 297 nm. Most importantly, this novel HPLC method is simple and selective enough to evaluate dasatinib and nilotinib content in the lipid nanocarriers.

ALK Inhibitor and Chemotherapy Combinations in Models of ALK-Translocated NSCLC.

Randomized trials have shown the benefit of combining tyrosine kinase inhibitors (TKI) and chemotherapy in the treatment of epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC). For anaplastic lymphoma kinase-rearranged (ALK+) NSCLC, prospective trial results of the combination are not available and have not even been thoroughly investigated in vitro. In this study, we investigated combinations of TKI and chemotherapy using in vitro models of ALK+ NSCLC. ALK+ cell line models H3122, H2228, and DFCI032 with differing primary resistance to ALK receptor TKIs were used. We investigated short-(viability assay) and long-term (colony-formation assay) cytotoxicity, apoptosis, and cell signaling in response to the combinations of agents. We selected the most commonly used agents, alectinib, cisplatin, and pemetrexed, to investigate the combination effects. In the combination experiments with short-term exposure, synergism between TKI and pemetrexed was observed, while cisplatin had antagonistic effects. In the long-term experiments, the combination of cisplatin and TKI was synergistic in all lines, while no synergism was observed with pemetrexed. Among the chemotherapy and TKI sequences, cisplatin followed by TKI was more cytotoxic than the opposite in two out of the three models. In the TKI-sensitive H3122 cell line, the combination of chemotherapy and TKI combination increased apoptosis. Interestingly, pemetrexed treatment resulted in the activation of ALK, which was abolished with TKI. Combining TKI and chemotherapy in ALK+ models has some synergistic effects that overcome primary TKI resistance. However, the synergy varies depending on the chemotherapeutic agent, cytotoxic assay, and the cell line used. Prospective clinical trials are warranted to fully characterize the potential of combination chemotherapy with TKIs in ALK+ NSCLC.

Hepatic artery infusion chemotherapy combined with immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced hepatocellular carcinoma with portal vein tumor thrombus: A single center retrospective study.

e16176 Background: Hepatic artery infusion chemotherapy (HAIC) combined with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs, a triplet regimen) has shown promising results in advanced hepatocellular carcinoma (HCC); however, the real world outcomes for pts with portal vein tumor thrombosis (PVTT) need further clarification. This study aimed to investigate the effectiveness of the triplet regimen in HCC pts with PVTT. Methods: We retrospectively included pts who received HAIC plus anti-PD-1 antibodies, bevacizumab or lenvatinib as first-line therapy for HCC pts with PVTT between Apr 2021 and Dec 2022. Pts received HAIC of mFOLFOX (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; 5-fluorouracil bolus, 400 mg/m2 on day 1; 5-fluorouracil infusion, 2400 mg/m2 for 46 h). The combination of TKIs and ICIs included 6 patterns: tislelizumab and lenvatinib (TIS-LEN), sintilimab and lenvatinib (SIN-LEN), pembrolizumab and lenvatinib (PEM-LEM), camrelizumab and lenvatinib (CAM-LEN), sintilimab and bevacizumab (SIN-BEV), and atezolizumab and bevacizumab (ATE-BEV). Primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. Results: A total of 113 pts were included, with a median age of 55 years (range 48-60). Pts characteristics were as follows: male (90.3%), hepatitis B (81.4%), BCLC C stage (100%), Child-Pugh A (92.9%), tumor number [ = 1 (45.1%), = 2 (10.6%), ≥3 (44.3%)], tumor diameter&gt;10 cm (43.4%), extrahepatic metastasis (19.5%), beyond up to steven status (88.5%). Specific treatment options are as follows: HAIC-TIS-LEN (n = 57), HAIC-SIN-LEN (n = 21), HAIC-PEM-LEM (n = 6), HAIC-CAM-LEN (n = 12), HAIC-SIN-BEV (n = 14), and HAIC-ATE-BEV (n = 3). As of Dec 31, 2023, the median follow-up duration was 18.4 mo (95% CI, 16.7-25.1), and the median number of HAIC was 2.5 (range 2-3). The median PFS was 8.1 months (95% CI, 6.8-9.8), while the median OS reached 17.7 months (95% CI:14.5-27.6). ORR was 51.3% (3 CR, 55PR), DCR was 91.2% per RECIST 1.1; ORR was 64.6% (18 CR, 55 PR), DCR was 92% per mRECIST. 15 pts (13.3%) received surgical treatment after conversion, 13 of whom remains tumor-free to date. Among those who develop disease progression, 35.3% pts (29/83) underwent a subsequent regimen that included TACE. The most common TRAEs were hypoalbuminemia (41.6%), abdominal pain (36.3%), anorexia (33.6%), hypertension (27.4%) and hypothyroidism (25.6%). The most common grade 3-4 TRAEs included hypertension (10.6%), leukocytes count decreased (9.7%), abdominal pain (8.8%), proteinuria (6.2%) and hypoalbuminemia (5.3%). Conclusions: This study further demonstrates the clinical benefit of HAIC plus ICIs and TKIs for HCC pts with PVTT. In the future, prospective studies are warranted.

Predictors of short-term death and long-term survival in advanced hepatocellular carcinoma (HCC) treated with contemporary tyrosine kinase inhibitors (TKI) or immunotherapy: A multicenter analysis from the HCC-CHORD consortium.

4098 Background: Advances in systemic therapy for HCC have increased treatment options, including TKIs and immunotherapy combinations. Variables that predict patient outcomes may be helpful in personalizing treatment decisions. The aim of this study was to identify predictors of short-term death (STD) and long-term survival (LTS) for HCC patients. Methods: Retrospective review of patients with advanced HCC who received a TKI or immunotherapy combinations was conducted between Aug 2018 to Aug 2022 in the Canadian provinces of British Columbia, Alberta, Nova Scotia, Manitoba, as well as from select institutions in Ontario (n = 2). Prior locoregional therapies were permitted. Variables examined were: Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh class, albumin-bilirubin (ALBI) grade, alpha fetoprotein (AFP) level, microvascular invasion (MVI), and distant metastases. Multivariate logistic regression was used to determine independent predictors of STD (patient survival &lt; 6 months vs others) and LTS (patient survival &gt; 18 months vs others). Results: 520 patients with the following baseline characteristics were included: median age 66, 84.6% male, 87.4% ECOG performance status 0-1, 69.7% BCLC stage C, and 88.7% Child-Pugh A. First-line treatments were primarily: lenvatinib 57.3%, sorafenib 8.1%, and atezolizumab/bevacizumab 31.7%. Median progression-free survival was 7.4 months (95% CI: 6.2 to 8.4), and overall survival was 17.1 months (95% CI:, 15.1 to 18.8). Independent predictors of STD were (odds ratio): ALBI grade (2.26), MVI (2.13), and distant metastases (2.14). These three factors were also predictive for LTS: ALBI grade (0.45), MVI (0.49), and distant metastases (0.36). Child-Pugh class, AFP, and BCLC stage were not predictive of STD nor LTS (Table). Conclusions: This study supports higher ALBI grade, MVI and distant metastases as predictors of STD, while lower ALBI grade, absence of MVI and lack of distant metastases were predictive of LTS in HCC patients treated with contemporary TKIs or immunotherapy combination regimens. These predictors may help guide treatment decisions in patient populations underrepresented in clinical trials, including patients with Child-Pugh B7 score who are often excluded. [Table: see text]

Tislelizumab plus tyrosine kinase inhibitor versus active surveillance in patients with ablated high-risk hepatocellular carcinoma: An open-label, parallel controlled, prospective cohort study.

e16238 Background: In IMbrave050, adjuvant atezolizumab plus bevacizumab demonstrated improvement in recurrence-free survival vs active surveillance in patients at high risk of hepatocellular carcinoma (HCC) recurrence following resection or ablation with curative intent. However, there is limited study on programmed cell death protein 1 (PD-1) inhibitor plus tyrosine kinase inhibitor (TKI) as postoperative adjuvant therapy for HCC. We aimed to assess the safety and efficacy of tislelizumab (a PD-1 inhibitor) plus TKI as adjuvant therapy versus active surveillance in patients at high risk of HCC recurrence after curative ablation. Methods: This study enrolled patients with HCC at high risk of recurrence following curative ablation. Patients were paralleled to Arm A (tislelizumab plus TKI) or Arm B (active surveillance). Patients in Arm A received tislelizumab (200 mg, IV, q3w) plus TKI for three months (4 cycles) following curative ablation, while those patients in Arm B underwent active surveillance. Primary endpoints were safety and tumor recurrence rate. Secondary endpoint was disease free survival (DFS). Exploratory endpoints included biomarkers related to the recurrence. Results: A total of 48 patients were enrolled with a median follow-up time of 283 days (IQR: 123-460 days, clinical cutoff date: 1 Jan 2024). Nine patients (37.5%) reported at least one adverse event of any degree in Arm A and three patients (12.5%) reported in arm B, most of which were mild. Only one patient in arm A experienced a grade 3 treatment-related adverse event, which improved after administration of symptomatic treatment. The recurrence rate of patients in arm A was 20.83%, which was significantly lower than the 58.3% in arm B (OR = 0.188 [95% CI: 0.052 - 0.674], P = 0.017). Four cycles of adjuvant tislelizumab plus TKI therapy was associated with significantly improved DFS (median, not evaluable [NE]) compared with active surveillance (median, 188 days [95% CI: 78.4 - 297.6 days]; HR = 0.396 [95% CI: 0161 - 0.973], P = 0.044). The absence of tislelizumab treatment (OR = 4.823 [95% CI: 1.091 - 21.329], P = 0.038) and multiple tumor lesions (OR = 7.651 [95% CI: 1.270 - 46.114], P = 0.026) were risk factors for recurrence of HCC after curative ablation. Conclusions: The safety of tislelizumab plus TKI combination therapy were generally manageable. Statistically significant and clinically meaningful improvement in tumor recurrence rate and DFS were seen in patients receiving combination therapy vs active surveillance. This study was a positive attempt to undergo short-course PD-1 inhibitor plus TKI combination therapy in patients with HCC at high risk of recurrence following curative ablation, showing promising efficacy in preventing HCC recurrence. Clinical trial information: NCT06059885 .

Emerging Treatment Options for Neuroendocrine Neoplasms of Unknown Primary Origin: Current Evidence and Future Perspectives.

Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9-22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. Chemotherapy represents the backbone for the treatment of high-grade poorly differentiated UPO-NENs, usually providing deep but short-lasting responses. Conversely, the spectrum of available systemic therapy options for well-differentiated UPO-NENs may range from somatostatin analogs in indolent low-grade tumors, to peptide receptor radioligand therapy, tyrosine kinase inhibitors (TKIs), or chemotherapy for more aggressive tumors or in case of high disease burden. In recent years, molecular profiling has provided deep insights into the molecular landscape of UPO-NENs, with both diagnostic and therapeutic implications. Although preliminary, interesting activity data have been provided about upfront chemoimmunotherapy, the use of immune checkpoint inhibitors (ICIs), and the combination of ICIs plus TKIs in this setting. Here, we review the literature from the last 30 years to examine the available evidence about the treatment of UPO-NENs, with a particular focus on future perspectives, including the expanding scenario of targeted agents in this setting.

Risk versus Benefit of Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma: ASystematic Review and Meta-Analysis of Randomized Controlled Trials.

Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.

Outcomes, responses, and prognostic analyses of intrathecal combined treatment for leptomeningeal metastasis from lung adenocarcinoma.

Leptomeningeal metastasis (LM) is a severe lung cancer complication, with potentially fatal consequences. The use of intrathecal therapy (IT) combined with systemic therapy has shown promise as a treatment approach for LM. Thus, this study aimed to evaluate the features and responses to IT combined therapy and identify determinants affecting patients with leptomeningeal metastasis resulting from lung adenocarcinoma (LM-LA). A retrospective analysis of medical records from our hospital database was performed, covering from April 2018 to August 2022, for 37 patients diagnosed with LM-LA and treated with IT combined therapy. Patients who received IT combined therapy for LM-LA were evaluated for demographic characteristics, treatment efficacy, survival, and variables that impacted them. The median overall survival (mOS) of 37 patients was 16.0 months, and the survival rates at 6 and 12 months were 75.7% and 35.1%, respectively. Among the 21 patients with LM-LA who received IT combined with tyrosine kinase inhibitors (TKIs), the mOS was 17.0 months, which was significantly longer than that of patients treated with IT combined with chemotherapy (7.0 months, P = 0.010) and the best supportive care (6.0 months, P = 0.001). However, no significant survival benefit was observed in patients treated with IT combined with TKIs when compared with those treated with IT combined with PD-1 (5.0 months, P = 0.249). Multivariate analysis indicated that the combination of TKIs was an independent favorable prognostic factor for patients with LM-LA. Combination treatment is regarded as an additional option for patients with LM-LA. Compared with other combination therapies in our study, IT combined with TKI therapy provided a better survival outcome for patients with LM-LA.

Abstract 4922: Unraveling sarcomatoid features in clear cell renal cell carcinoma with RNA-seq

Abstract Introduction: Sarcomatoid сlear cell renal cell carcinoma (ccRCC) represents a challenging and aggressive subset of kidney cancers with poor prognosis and resistance to conventional treatments. Recent studies have shown the benefit of checkpoint inhibitors (CPIs) for patients with sarcomatoid components; therefore, precise and objective evaluation of sarcomatoid differentiation is essential for CPI selection. Here, we developed a predictive model to identify sarcomatoid features in ccRCC. Methods: The machine learning-based transcriptomic sccRCC model was developed on 512 samples from publicly available datasets: TCGA-KIRC and CPTAC-ccRCC. Samples were excluded with the following criteria: inconsistent with ccRCC, less than 10% sarcomatoid component, or &amp;lt;20% tumor neoplastic cellularity. Sarcomatoid features for each case were assessed by 3 pathologists. The meta-cohort was divided into training (n = 348) and validation (n = 164) cohorts.The model was tested on a publicly available cohort of ccRCC patients from Sato et al. (n = 100). Clinical validation was performed using an additional prospective cohort that received BostonGene’s Tumor PortraitTM test (n = 32) with RNA-seq and whole exome sequencing (WES). The JAVELIN Renal 101 cohort was used to uncover differences in progression-free survival (PFS) associated with a predicted sarcomatoid component in advanced or metastatic ccRCCs treated with a combination of CPIs and tyrosine kinase inhibitors (TKIs). Results: H&amp;E analysis of the TCGA, CPTAC, and BostonGene cohorts identified zones with sarcomatoid features in 129 out of 556 (23.2%) samples. The sarcomatoid predictive model demonstrated robust performance, with weighted F1-scores of 0.85 when applied to the test cohort (Sato et al.) and 0.70 for the prospective clinical cohort. The model accurately classified 9 out of 10 total sarcomatoid samples in the prospective clinical cohort, highlighting its potential for real-world clinical applications. When applied to TCGA validation samples, sarcomatoid patients identified by the transcriptomic model exhibited median overall survival (mOS) of 55 months, whereas sarcomatoid patients based on H&amp;E assessment had a mOS of 67 months, indicative of the model’s superior performance when detecting sarcomatoid features for OS prediction. Moreover, the sarcomatoid ccRCCs predicted by transcriptomic model that were treated with a combination of CPIs and TKIs had statistically (p=0.0001) improved PFS compared to the TKI-treated group. Conclusion: The developed transcriptomic model effectively differentiated sarcomatoid from non-sarcomatoid ccRCC samples with robust performance metrics. With additional investigation, the predictive value of the sarcomatoid ccRCC transcriptomic model can be leveraged to guide CPI and TKI selection. Citation Format: Kirill Kryukov, Suren Davitavyan, Danil Stupichev, Anna Sharun, Anna Love, Mikhail Kleimenov, Stepan Kuznetsov, Arina Tkachuk, Vladimir Kushnarev. Unraveling sarcomatoid features in clear cell renal cell carcinoma with RNA-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4922.

Abstract 5145: Association of a ctDNA biomarker of treatment response with clinical outcomes in a real-world pan-cancer cohort treated with tyrosine kinase inhibitors

Abstract Clinical evidence suggests that early changes in circulating tumor DNA tumor fraction (ctDNA TF) is predictive of patient response to immune checkpoint inhibitors, but the extent to which this approach can be used for patients on Tyrosine Kinase Inhibitors (TKIs) is not known. Here, we use xF Monitor to estimate ctDNA TF in patients that received TKIs and show that changes in circulating TF correlate with outcomes in a real-world pan-cancer cohort. Tempus xF Monitor is a ctDNA assay that measures quantitative molecular changes in ctDNA TF by utilizing diverse genomic events, dynamically weighting somatic variant allele frequencies and copy number variants, while using germline information to inform these estimates and providing single nucleotide variant (SNV) results on 105 genes. Molecular responders (MR) were defined as patients with ≥50% reduction in ctDNA TF between baseline and on-treatment time points, consistent with our previously established threshold. Deidentified patient records from the Tempus multimodal database were analyzed if patients had an xF test ≤ 15 weeks prior to the start of their first TKI regimen and an xF test 15 -180 days post-TKI initiation. Patients received TKI agents as classified in the Tempus Medical Ontology, which assigns a unique ID to key clinical concepts, validated and harmonized across industry standard terminologies. The TKI list was further validated using the NCI Metathesaurus (https://ncim.nci.nih.gov/ncimbrowser/) TKI concept (NCI Code C1967). Clinical endpoints were defined from TKI start to the first progression event or death (rwPFS) or death (rwOS), both censored on the last follow-up in event-free patients. Kaplan Meier analysis and Cox proportional hazard models were fitted to compare MR status and survival outcomes on TKI. The evaluable pan-cancer cohort N=69, median age = 61.5 yo, advanced/metastatic disease = 72%, 65% were female, consisted of &amp;gt; 10 cancer diagnoses (35% NSCLC, 26% BC), 41% 1L. In this cohort, 49% of patients received a TKI combination regimen, 21% with CT, 18% with ICI. 68% of patients with NGS testing received matched targeted mutation therapies based on NCCN guidelines. Patients classified as MR based on xF Monitor results had improved survival outcomes with a median rwOS of 951 days (vs 439 days for non-MRs). MR patients had significantly longer rwPFS (HR = 0.383, p = 0.005, CI = 0.12 - 0.75) and rwOS (HR = 0.205, p = 0.004, CI = 0.07 - 0.61) than non-MRs. xF Monitor is a novel tumor naive serial quantitative ctDNA TF algorithm off the Tempus xF assay that has the potential to be used clinically as a monitoring biomarker to stratify patients who are likely to benefit from TKI therapy. xF monitor can be used as a strategy to identify patients at a high risk of progression who could benefit from early switch or intensifying therapy. Results need to be prospectively validated in a larger cohort. Citation Format: Akash Mitra, John Guittar, Regina Schwind, Terri Driessen, Matthew Berginski, Christine Lo, Michelle M. Stein, Jonathan Freaney, Seung Won Hyun, Chithra Sangli, Kate Sasser, Halla Nimeiri, Aadel Chaudhuri. Association of a ctDNA biomarker of treatment response with clinical outcomes in a real-world pan-cancer cohort treated with tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5145.

Transarterial chemoembolization with/without immune checkpoint inhibitors plus tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: a single center, propensity score matching real-world study

ObjectivesTo explore the efficacy and safety of Transarterial chemoembolization (TACE) in combination with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in patients with unresectable hepatocellular carcinoma (uHCC).Methods456 patients with HCC receiving either TACE in combination with ICIs and TKIs (combination group, n = 139) or TACE monotherapy (monotherapy group, n = 317) were included from Apr 2016 to Dec 2021 in this retrospective study. We employed propensity score matching (PSM), performed 1:2 optimal pair matching, to balance potential bias.ResultsThe mean follow-up time is 24.7 months (95% CI 22.6–26.8) for matched patients as of March 2022. After matching, the combination group achieved longer OS and PFS (median OS:21.9 vs. 16.3 months, P = 0.022; median PFS: 8.3 vs. 5.1 months, P < 0.0001) than TACE monotherapy group. The combination group had better objective response rate (ORR) and disease control rate (DCR) (ORR: 52.5% vs. 32.8%, P < 0.001; DCR: 82.7% vs. 59.6%, P < 0.001). Subgroup analysis showed that patients who received “TKIs + ICIs” after the first TACE procedure (after TACE group) achieved longer OS than those before the first TACE procedure (before TACE group) (26.8 vs. 19.2 months, P = 0.011). Adverse events were consistent with previous studies of TACE-related trials.ConclusionsTACE plus TKIs and ICIs appeared to deliver longer PFS and OS in HCC patients than TACE monotherapy. “TKIs + ICIs” co-treatment within 3 months after the first TACE procedure might be a better medication strategy.