Combination Of Bevacizumab Research Articles

Hemophagocytic lymphohistiocytosis following pembrolizumab and bevacizumab combination therapy for cervical cancer: a case report and systematic review

BackgroundProgrammed cell death protein 1 (PD-1) checkpoint inhibitors such as pembrolizumab are novel therapeutics used to treat various advanced malignancies. Immune-related adverse events are common, among the most serious of these toxicities is hemophagocytic lymphohistiocytosis (HLH), which is a life-threatening disorder of unbridled immune activation but has not been properly established.MethodsWe have procured the first case of hemophagocytic lymphohistiocytosis as an aftermath of treatment with pembrolizumab from the Sir Run Run Shaw Hospital, Zhejiang University, China. In a pursuit to enhance the understanding of this condition, a comprehensive systematic review was performed encompassing all reported instances of ICI-associated Hemophagocytic lymphohistiocytosis within the realms of PubMed and Embase databases.ResultsWe detail the recovery of a cervical cancer patient with a history of psoriasis who developed HLH after combined pembrolizumab and bevacizumab treatment. Remarkably, tumor lesions exhibited substantial and sustained regression. From an analysis of 52 identified Immune Checkpoint Inhibitor (ICI)-related HLH cases, we discovered that HLH often occurred within the first two treatment cycles and approximately 20% of these patients had a history of autoimmune-related diseases. Despite a 15% mortality rate, the majority of patients experienced positive outcomes. Notably, in instances of recovery from HLH, 80% showed positive tumor outcomes. Even after discontinuation of ICI treatment, tumor control persisted in some cases.ConclusionWe identified the first case of HLH caused by ICI treatment in cervical cancer and summarized the possible occurrence factors of these cases, the treatment outcomes of HLH, and the impact on tumor outcomes.

Health-related quality of life and its influencing factors among lung cancer patients receiving immune checkpoint inhibitors: A cross-sectional study

PurposeThe aim of this study was to examine the level of health-related quality of life (HRQOL) of lung cancer patients receiving immune checkpoint inhibitors (ICIs) and analyze its influencing factors. MethodA cross-sectional study was conducted. From April 2022 to March 2023, 560 lung cancer patients receiving ICIs at three medical bases in Guangzhou, China were recruited using a convenient sampling method. A general information questionnaire, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), the Social Support Rating Scale (SSRS) and the Medical Coping Modes Questionnaire (MCMQ) were used for collecting data on sociodemographic and clinical characteristics, HRQOL, social support and medical coping mode. A descriptive analysis was conducted to describe HRQOL. Multiple regression analysis was applied to determine the factors influencing HRQOL. ResultsFor lung cancer patients receiving ICIs, the mean score of HRQOL was 59.21 ± 19.86. Multivariate analysis indicated that acceptance-resignation coping mode (β = −0.37, P < 0.01), Eastern Cooperative Oncology Group (ECOG) score (β = −0.35, P < 0.01), combination of chemotherapy and/or bevacizumab (β = −0.14, P < 0.01), and subjective support (β = 0.07, P = 0.04) all contributed to 42.7% of the variance in HRQOL of the patients receiving ICIs. ConclusionsIt is imperative to address and resolve the HRQOL issue for lung cancer patients receiving ICIs. The findings suggest nurse practitioners should be aware of a variety of factors that influence HRQOL and provide tailored inventions to patients as early as possible to help them achieve better HRQOL.

Evaluating combined bevacizumab and XELOX in advanced colorectal cancer: Serum markers carcinoembryonic antigen, carbohydrate antigen 125, carbohydrate antigen 199 analysis.

Colorectal cancer ranks third and second among common and fatal cancers. The treatment of metastatic colorectal cancer (mCRC) is generally based on XELOX in clinical practice, which includes capecitabine (CAP) and oxaliplatin. Serum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 125 and CA199 are prognostic factors for various tumors. To investigate evaluating combined bevacizumab (BEV) and XELOX in advanced colorectal cancer: Serum markers CEA, CA125, CA199 analysis. In this retrospective study, a total of 94 elderly patients diagnosed with mCRC were recruited and subsequently categorized into two groups based on the distinct treatment modalities they received. The control group was treated with XELOX plus CAP (n = 47), while the observation group was treated with XELOX plus CAP and BEV (n = 47). Several indexes were assessed in both groups, including disease control rate (DCR), incidence of adverse effects, serum marker levels (CEA, CA125, and CA19) and progression-free survival (PFS). After 9 wk of treatment, the serum levels of CEA, CA199 and CA125 in the observation group were significantly lower than those in the control group (P < 0.05). Moreover, the PFS of the observation group (9.12 ± 0.90 mo) was significantly longer than that of the control group (6.49 ± 0.64 mo). Meanwhile, there was no statistically significant difference in the incidence of adverse reactions and DCR between the two groups during maintenance therapy (P > 0.05). On the basis of XELOX treatment, the combination of BEV and CAP can reduce serum tumor marker levels and prolong PFS in patients with mCRC.

Dual Role of Necroptosis in Cervical Cancer: Promoting Tumor Aggression and Modulating the Immune Microenvironment via the JAK2-STAT3 Pathway.

In the dynamic landscape of cervical cancer (CC) pathophysiology, this study aimed to elucidate the role of necroptosis in modulating tumor proliferation, invasion, and the immune microenvironment in CC. In this study, the impact of necroptosis on CC was evaluated through a series of bioinformatical analyses and experimental approaches. The impact of necroptosis on CC was illustrated by analyzing its effects on tumor aggression, immune responses, and the JAK2-STAT3 signaling pathway. Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), was also evaluated for its potential induction of necroptosis in CC cells and its interaction with necroptosis inhibitors. Additionally, the study assessed the influence of necroptosis on the immune microenvironment, particularly in T-cell-related pathways and the expression of tumor suppressor genes in CC. Necroptosis was found to enhance VEGFA expression through the activation of the JAK2-STAT3 pathway, promoting tumor proliferative and invasive capabilities in CC. Bevacizumab induced necroptosis in CC cells, potentially leading to resistance to therapy. The combination of bevacizumab with necroptosis inhibitors attenuated VEGFA expression, suggesting a novel therapeutic strategy. Additionally, necroptosis activated T-cell-related pathways and promoted the infiltration and activation of Jurkat T cells. CD3D-a tumor suppressor gene in CC-was identified as a critical marker and its expression could be upregulated by necroptosis via the JAK2-STAT3 pathway in Jurkat T cells. Treatment of CC cells with supernatants from necroptosis-induced Jurkat cells resulted in reduced tumor cell proliferation and invasion. This study reveals a complex interaction between necroptosis, tumor progression, and the immune response in CC. The findings propose a nuanced approach to leveraging necroptosis for therapeutic interventions, highlighting the potential of combining necroptosis inhibitors with existing therapies to improve treatment outcomes in CC.

Comparison of the Efficiency and Safety of Photodynamic Therapy Combined Intravitreal Bevacizumab and Intravitreal Triamcinolone Treatments in Age-Related Macular Degeneration

Objective: This study aims to retrospectively examine the mid and long-term results of the photodynamic therapy (PDT) +IVTA group and the PDT +IVB applied Group in the treatment of choroid neovascularization (CNV) due to age-related macular degeneration (AMD) and to compare the results with the results of multicenter clinical studies. Materials and Methods: 64 eyes of 64 patients admitted to Haseki Training and Research Hospital, Department of Ophthalmology, Retina unit between June 2003 and March 2009, diagnosed with CNV secondary to age-related macular degeneration and treated, were included in the study. Thirty-five eyes with PDT +IVTA were classified as Group I, and 29 with PDT +IVTA were classified as Group II. Visual acuities of the cases were evaluated with ETDR and Snellen charts and converted to their equivalents on the Logarithm of Minimal Angle of Resolution (logMAR) scale. All patients underwent an ophthalmological examination before and after the treatment; fundus fluorescein angiography (FFA) and optical coherence tomography (OCT) were performed to see if there was any recurrence in the patients. Patients who were found to have relapsed were re-treated. Results: There were 26 (40.6%) female cases and 38 (59.4%) male cases. The ages ranged from 55 to 88, with a mean age of 73.85±7.26. The follow-up period of the patients ranged from 5 months to 69 months; the mean was 17.65±13.48 months. When evaluated according to FFA images, 40 (62.5%) were occult, 12 (18.8%) were minimal-classical, and 12 (18.8%) were dominant-classical. After treatment, visual acuity decreased in 20% of the PDT +IVTA group and increased or remained the same in 80%. In the PDT +IVB group, blurred vision decreased by 27.6% and increased or remained the same by 72.4%. There was no statistically significant difference between the groups regarding the change in visual acuity after treatment compared to before treatment (p&gt;0.05). In OCT, the decrease in the mean central foveal thickness (CFT) after treatment compared to the mean CFT before treatment in Group I was statistically significant (p&lt;0.05). In Group II - the decrease in the mean CFT after treatment compared to the mean CFT before treatment was statistically significant (p&lt;0.01). In Group I, there was no statistically significant change in the mean lesion diameter after treatment compared to the mean lesion diameter before treatment (p&gt;0.05). However, the decrease in Group II was statistically significant (p&lt;0.01). While the increase in CFT (central foveal thickness) and lesion diameter was more pronounced in the PDT+IVTA group post-treatment compared to the pre-treatment group, no significant difference was observed in visual acuity change within the PDT+IVTA group. Conclusion: In the treatment of choroidal neovascularization secondary to age-related macular degeneration, the combination of Triamcinolone or Bevacizumab with photodynamic therapy has proven to be both effective and safe. This approach helps preserve the current vision and even enhance visual outcomes. Combination therapy reduces the frequency and number of monotherapies used to achieve visual success.

Aggressive pituitary tumors and carcinomas: medical treatment beyond temozolomide.

Aggressive pituitary tumors are a subset of pituitary neoplasms, characterized by unusually fast growth rate, invasiveness and overall resistance to optimized standard treatment. When metastases are present, the term pituitary carcinoma is employed. After failure of standard treatments, current guidelines recommend first-line temozolomide monotherapy. However, a significant number of patients do not respond to temozolomide, or experience disease progression following its discontinuation; in these latter cases, re-challenge with temozolomide is generally advised, although the reported outcomes have been less satisfactory. Although no alternative therapies have been formally recommended after temozolomide failure, growing evidence regarding potential second- or third-line therapeutic strategies has emerged. In the present work, we reviewed the available evidence published up to April 2023 involving the most relevant therapies employed so far, namely immune checkpoint inhibitors, bevacizumab, peptide radionuclide receptor therapy, tyrosine kinase inhibitors and mTOR inhibitors. For each treatment, we report efficacy and safety outcomes, along with data regarding potential predictors of response. Overall, immune checkpoint inhibitors and bevacizumab are showing the most promise as therapeutic options after temozolomide failure. The former showed better responses in pituitary carcinomas. Peptide radionuclide receptor therapy has also showed some efficacy in these tumors, while tyrosine kinase inhibitors and mTOR inhibitors have exhibited so far limited or no efficacy. Further studies, as well as an individualized, patient-tailored approach, are clearly needed. In addition, we report an unpublished case of a silent corticotroph pituitary carcinoma that progressed under dual immunotherapy, and then showed stable disease under a combination of lomustine and bevacizumab.

A case of secondary immune thrombocytopenia induced by atezolizumab plus bevacizumab therapy for hepatocellular carcinoma resulting in death from intracranial hemorrhage

An 84-year-old woman underwent laparoscopic partial hepatectomy for a single 3.0-cm-diameter nodule of hepatocellular carcinoma at segment 5. Although the postoperative condition was uneventful, multiple recurrences were observed six months after hepatic resection. Transcatheter arterial chemoembolization (TACE) was the second-line therapy. However, she was later diagnosed as TACE refractory due to residual tumor and presence of portal vein tumor thrombus. Third-line therapy was the combination of atezolizumab and bevacizumab, which was discontinued after 22 courses due to disease progression. Two months after the conclusion of chemotherapy, sudden onset of purpura was observed around her eyes and on her lower legs. Laboratory tests revealed severe thrombocytopenia, and she was diagnosed with secondary immune thrombocytopenic purpura. Steroids and immunoglobulin therapy were then administered. Although the immature platelet fraction increased after treatment, the platelet count did not. The patient died of intracranial hemorrhage 10 days after initiation of steroid and immunoglobulin therapy.

Bevacizumab Alone Versus Bevacizumab Plus Irinotecan in Patients With Recurrent Glioblastoma: A Nationwide Population-Based Study.

For treating recurrent glioblastoma, for which there is no established treatment, the antiangiogenic antibody, bevacizumab, is used alone or with irinotecan. This study was aimed at comparing the survival of patients with recurrent glioblastoma receiving bevacizumab monotherapy and those receiving bevacizumab plus irinotecan combination therapy (B+I) by using a nationwide population-based dataset. Patients matching the International Classification of Diseases code C71.x were screened from the Health Insurance Review and Assessment Service database. From January 2008 to November 2021, patients who underwent surgery or biopsy and subsequent standard concurrent chemoradiation with temozolomide were included. Among them, those who received bevacizumab monotherapy or B+I were selected. Demographic characteristics, inpatient stay, prescription frequency, survival outcomes, and steroid prescription duration were compared between these two groups. Eight hundred and forty-six patients who underwent surgery or biopsy and received concurrent chemoradiotherapy with temozolomide were included. Of these, 450 and 396 received bevacizumab monotherapy and B+I, respectively. The corresponding median overall survival from the initial surgery was 22.60 months (95% confidence interval [CI], 20.50-24.21) and 20.44 months (95% CI, 18.55-22.60; P = 0.508, log-rank test). The B+I group had significantly more bevacizumab prescriptions (median 5 times; BEV group: median 3 times). Cox analysis, based on the postsurgery period, revealed that male sex (hazard ratio [HR], 1.28; P = 0.002), older age (HR, 1.01; P = 0.042), and undergoing biopsy instead of surgery (HR, 1.79; P < 0.0001) were significantly associated with decreased survival. Fewer radiotherapy cycles correlated with improved survival outcomes (HR, 0.63; P = 0.001). Cox analysis, conducted from the start of chemotherapy including bevacizumab, showed that male sex was the only variable significantly associated with decreased survival (HR, 1.18; P = 0.044). We found no significant difference in overall survival between the bevacizumab monotherapy and B+I groups. Considering the additional potential toxicity associated with irinotecan, bevacizumab monotherapy could be a suitable treatment option for treating recurrent glioblastoma.

Promising Remission with Reduced Bevacizumab and Pembrolizumab Dosage in a Patient with AT-rich Interaction Domain 1A Mutated Ovarian Clear-cell Carcinoma Refractory to Chemotherapy

Abstract Patients with ovarian clear-cell carcinoma have limited treatment choices, because they are resistant to the standard chemotherapeutic agents used in ovarian cancer. The phase II KEYNOTE-100 trial revealed that pembrolizumab monotherapy demonstrated a 15.8% objective response in patients with ovarian clear-cell carcinoma in the subgroup analysis, which is much higher than that of other histology subtypes of ovarian cancer. Immune checkpoint inhibitors may play a new role in the treatment of these malignancies. Genetic analyses revealed a significant proportion of ovarian clear-cell carcinoma carrying the AT-rich interaction domain 1A protein (ARID1A) mutation. The association between a higher frequency of ARID1A mutation and a higher response to immune checkpoint inhibitors in ovarian clear-cell carcinoma opens a new research topic. Herein, we report a patient with ovarian clear-cell carcinoma refractory to platinum-based chemotherapy, who was treated with a reduced dose of bevacizumab and pembrolizumab combination therapy and achieved a complete treatment response.

Efficacy of atezolizumab–bevacizumab combination therapy early after recurrence of hepatocellular carcinoma following resection or ablation with a curative intent

Efficacy of atezolizumab–bevacizumab combination therapy early after recurrence of hepatocellular carcinoma following resection or ablation with a curative intent

Atezolizumab and Bevacizumab Combination Therapy in the Treatment of Advanced Hepatocellular Cancer.

Liver cancer, particularly hepatocellular carcinoma, is a global concern. This study focuses on the evaluation of Atezolizumab and Bevacizumab combination therapy as a promising alternative in the treatment of advanced hepatocellular carcinoma. The objectives of this systematic review include evaluating the efficacy of Atezolizumab and Bevacizumab combination therapy compared to conventional therapies with Sorafenib and other conventional therapies, analyzing the associated adverse effects, and exploring prognostic factors in the setting of advanced hepatocellular carcinoma. A systematic literature review was carried out using the PubMed and Web of Science databases. Fifteen related articles were included and evaluated according to their level of evidence and recommendation. Results: The combination therapy of Atezolizumab and Bevacizumab, along with Sorafenib, showed positive results in the treatment of patients with advanced hepatocellular carcinoma. Significant adverse effects were identified, such as gastrointestinal bleeding, arterial hypertension, and proteinuria, which require careful attention. In addition, prognostic factors, such as transforming growth factor beta (TGF-β), alpha-fetoprotein (AFP), and vascular invasion, were highlighted as key indicators of hepatocellular carcinoma progression. Conclusions: The combination of Atezolizumab and Bevacizumab is shown to be effective in the treatment of advanced hepatocellular carcinoma, although it is essential to take into consideration the associated adverse effects. The prognostic factors identified may provide valuable information for the clinical management of this disease. This study provides a comprehensive overview of a promising emerging therapy for liver cancer.

Effect of bevacizumab in combination with chemotherapy for ovarian cancer on wound healing in patients: Ameta-analysis.

In this meta-analysis, we reviewed the findings and definitive findings of a new study that assessed the impact of bevacizumab on wound healing following combined chemotherapy for ovarian cancer (OC). The results of a controlled study that assessed the efficacy of bevacizumab in the treatment of ovarian cancer were retrieved from 4 databases, such as the Web of Science and EMBASE. The results of the adverse event associated with wound healing were determined by comparison of the controlled studies of bevacizumab plus chemotherapy in the treatment of ovarian cancer. A meta-analysis was conducted with either a randomized or a fixed-effect model in order to establish an odds ratio for time to event variables and for a binary outcome. In the research literature, 830 trials have been identified and seven have been chosen to be included in a definitive analysis of the trial. Among the 4134 cases who received chemotherapy after operation, 2098 received standard chemotherapy and 2036 received the addition of bevacizumab. A total of 7 trials have shown that the use of bevacizumab in the treatment of ovarian cancer patients has reduced wound healing (OR, 0.55; 95% CI: 0.37, 0.80, p = 0.002). Four trials demonstrated that there was no change in the incidence of haemorrhage in patients with ovarian cancer when administered with or without bevacizumab (OR, 0.48; 95% CI, 0.10, 2.34, p = 0.37). The combined use of bevacizumab and chemotherapy may have a negative effect on the healing of wound.

Efficacy of Atezolizumab Plus Bevacizumab Versus Lenvatinib in Patients with Unresectable Hepatocellular Carcinoma: a Meta-analysis.

Hepatocellular carcinoma is a lethal disease and there has been a debate regarding the first-line treatment of its advanced and unresectable form. Observational studies have explored atezolizumab plus bevacizumab versus lenvatinib, yielding mixed results. This systematic review and meta-analysis aim to compare efficacy and safety of both treatment arms. A systematic literature review was conducted in accordance with PRISMA guidelines. Randomized control trials, cohort studies, or case-control that included patients above age 60 with unresectable hepatocellular carcinoma confirmed by radiological imaging were included. At least one of the outcomes: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response, or adverse events was included in the selected studies. Ten cohorts were included in the analysis with a total of 6493 patients. Nine of the included studies had patients with advanced HCC (BCLC-C) or intermediate HCC (BCLC-B) and 1 study included patients with all three stages (BCLC-A, BCLC-B, and BCLC-C). Of these patients, 2524 patients received atezolizumab plus bevacizumab (A + B) combination while 3969 received lenvatinib. The overall survival was better statistically in the A + B group then the lenvatinib group (MD: - 5.06; 95% CI: - 7.79 to - 2.33; p = 0.0003, I2 = 0%). The progression-free survival was significantly improved in A + B arm as well group (MD: - 4.96; 95% CI: - 7.67 to - 2.26; I2 = 0%, p = 0. 0003). There was no significant difference in objective response rate, disease control rate, and frequency of adverse events in either of the group. Our study concluded that combination therapy with atezolizumab plus bevacizumab could increase the survival duration without affecting the disease course. Moreover, while the severity of adverse events was greater in the A + B group, their frequency was comparable to the lenvatinib group.

Atezolizumab and bevacizumab for non-resectable or metastatic combined hepatocellular-cholangiocarcinoma: Amulticentric retrospective study.

The efficacy of atezolizumab/bevacizumab has never been reported in patients with metastatic/unresectable combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We retrospectively included patients with a histological diagnosis of unresectable/metastatic cHCC-CCA and treated with atezolizumab/bevacizumab (2020-2022) in 7 centers. Clinical and radiological features were collected at the beginning of atezolizumab/bevacizumab. We reported the radiological response using RECIST criteria, overall survival (OS) and progression-free survival (PFS). Sixteen patients with cHCC-CCA were included and were predominantly male (75%) with advanced fibrosis/cirrhosis (69%). Nine patients received atezolizumab/bevacizumab as a first-line systemic treatment, 5 as a second line, 1 as a third line and 1 as a fifth line. Severe digestive bleeding occurred in 2 patients. Among the 9 patients treated in the first line, 4 experienced radiological progression, 3 partial response and 1 had stable disease. Patients treated with atezolizumab/bevacizumab in the first line had a median OS of 13months and a median PFS of 3months. Among the 7 patients receiving atezolizumab/bevacizumab as a second line or more, 4 patients harbored a stable disease, 2 a partial response, and 1 a progressive disease. The combination of atezolizumab and bevacizumab showed signs of anti-tumor efficacy in patients with unresectable/metastatic cHCC-CCA.

Metronomic Temozolomide (mTMZ) and Bevacizumab-The Safe and Effective Frontier for Treating Metastatic Neuroendocrine Tumors (NETs): A Single-Center Experience.

Addressing the persistent challenges in treating metastatic neuroendocrine tumors (NETs) demands ongoing refinement and innovation in therapeutic strategies. This study investigates the potential advantages of combining metronomic temozolomide (mTMZ) with bevacizumab for patients diagnosed with metastatic NETs, particularly focusing on those with a Ki-67 index under 55%. Data from 30 patients were analyzed, using key performance indicators such as progression-free survival (PFS), overall survival (OS), and response rates to therapy, to gauge the treatment's efficacy. The results were encouraging: the median PFS recorded was 16.3 months, and the OS was 25.9 months. The disease control rate (DCR) reached an impressive 86.7%, and the objective response rate (ORR) stood at 63.3%. The treatment regimen was well-tolerated, with no reported instances of grade 4 toxicities. Such a safety profile indicates that this regimen may be particularly advantageous for older, fragile patients who might struggle with conventional dosage levels. These initial findings suggest that the mTMZ and bevacizumab combination could potentially rival the conventional temozolomide-capecitabine therapy in managing metastatic NETs. We aimed to meticulously assess the efficacy of the mTMZ and bevacizumab combination in treating metastatic NETs. Given the initial promising results, a more conclusive understanding of its efficacy will require further research through larger, multicenter prospective clinical trials.

Risks of hypertension and thromboembolism in patients receiving bevacizumab with chemotherapy for colorectal cancer: A systematic review and meta-analysis.

Guidelines show that for metastatic colorectal cancer (mCRC), a combination of three-drug regimens, fluorouracil, leucovorin, and oxaliplatin and bevacizumab (BVZ), is one of the first-line standard therapies. BVZ is generally well tolerated; however, it is associated with infrequent, life-threatening side effects such as severe hypertension (HTN) (5%-18%), Grade ≥3 arterial thromboembolism (ATE) (2.6%), Grade ≥3 hemorrhagic events (1.2%-4.6%), and gastrointestinal perforation (0.3%-2.4%). This meta-analysis aims to evaluate the additive risk of BVZ-induced severe HTN and thromboembolism when BVZ is combined with a standard chemotherapy regime in patients with mCRC. Our search was conducted from January 29, 2022, to February 22, 2022, through databases of PubMed, clinicaltrial.gov, EMBASE, Web of Science, and Cochrane Library. Data analysis from randomized controlled trials (RCTs) and clinical trials was conducted using Review Manager V.5.4, comparing BVZ-chemotherapy to chemotherapy only, focusing on cardiovascular AE such as HTN and arterial and venous thromboembolism. The analysis from 26 clinical trials and RCTs showed that the odds of HTN were about four times higher, and ATE subgroup analysis of 11 studies showed over two times higher odds of ATE in patients being treated with BVZ compared to the chemotherapy-only group. BVZ, when added to the standard chemotherapy regimen for mCRC, was associated with higher odds of developing HTN and thromboembolism, specifically ATE, than the chemotherapy-only group. Our findings are significant as they provide vital information in analyzing the risk-benefit ratio of adding BVZ to the standard chemotherapy regime in patients with mCRC, especially in patients with vascular comorbidities.

Abstract B087: CTNNB1 mutations can mediate resistance to EGFR targeted therapies in Non-Small Cell Lung Cancer

Abstract Resistance to targeted therapy remains an ongoing challenge in lung cancer. β-Catenin (CTNNB1) mutations are observed in lung cancer, often co-occurring with known oncogenic alterations such as EGFR/KRAS/ALK. Oncogenic CTNNB1 mutations disrupt the β-catenin destruction complex upregulating Wnt signaling that may cause resistance to therapies targeting oncogenic drivers. An example of this was identified in post-mortem donated NSCLC tissue of a patient treated with a combination of carboplatin, pemetrexed, and bevacizumab that harbored both an acquired CTNNB1-T41A mutation and an EGFR exon 20 insertion. In addition, the CTNNB1 mutation spectrum was analyzed in lung cancer patients at Moffitt Cancer Center to identify prevalent CTNNB1 mutations for functional analyses. T41A, along with the most frequent Exon 3 CTNNB1 mutations were selected and transduced into HCC827 mutant cell lines to determine their ability to drive resistance to targeted therapies. Subsequently, western blotting and RNA sequencing were performed to assess differences between cells expressing wild-type and the most-resistant CTNNB1 mutant. A viability screen was also performed in which these cells were treated with a panel of drugs with known targets (COCKTAIL), in combination with EGFR TKI erlotinib, to identify new vulnerabilities of this CTNNB1 mutant erlotinib-resistant cells. Our data indicate that some CTNNB1 mutations, T41A, S37F, S45C and D32H, can cause resistance to EGFR inhibitor therapy, while others, D32Y, S33C, S33Y, S45P, and S37C, do not. Western blot analysis shows corresponding stabilization and higher accumulation of active β-catenin in cells expressing CTNNB1 mutants that are resistant to erlotinib. Of the mutations tested, cells expressing CTNNB1 T41A demonstrated the strongest resistance to erlotinib. Further analysis reveals higher levels of β-catenin regulated proteins, like axin2 and survivin, as well as EMT markers, such as vimentin and N-cadherin, in HCC827 CTNNB1 T41A cells when compared to the HCC827 CTNNB1 WT. Pathway analysis of genes differentially expressed between the WT and T41A mutant cells reveal WNT pathway to be the top upregulated pathway in the mutant cells. HCC827 T41A also showed sustained ERK, AKT and GSK3β signaling, and lower PARP cleavage compared to wild type, which may explain the resistance to EGFR TKI seen in these cells. COCKTAIL screening, comparing drug sensitivities of the WT and T41A mutant HCC827 cells to erlotinib in combination with various other targeted agents, identified PI3K, mTOR and MEK inhibitors that can reverse erlotinib resistance in the HCC827 CTNNB1 T41A cells. Our data suggests that CTNNB1 may be an important co-occurring alteration in developing resistance to targeted EGFR therapy. However, we show that different CTNNB1 mutations have differing abilities to drive resistance to EGFR TKI which correlates with the level of stabilization and activation of CTNNB1 and its downstream targets by these mutations. Citation Format: Anurima Majumder, Liznair Bridenstine, Benjamin Meyer, Fumi Kinose, J. Kevin Hicks, Theresa A Boyle, Eric B Haura. CTNNB1 mutations can mediate resistance to EGFR targeted therapies in Non-Small Cell Lung Cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B087.

PD-1- CD45RA+ effector-memory CD8 T cells and CXCL10+ macrophages are associated with response to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma

The combination of atezolizumab plus bevacizumab (atezo/bev) has dramatically changed the treatment landscape of advanced HCC (aHCC), achieving durable responses in some patients. Using single-cell transcriptomics, we characterize the intra-tumoural and peripheral immune context of patients with aHCC treated with atezo/bev. Tumours from patients with durable responses are enriched for PDL1+ CXCL10+ macrophages and, based on cell–cell interaction analysis, express high levels of CXCL9/10/11 and are predicted to attract peripheral CXCR3+ CD8+ effector-memory T cells (CD8 TEM) into the tumour. Based on T cell receptor sharing and pseudotime trajectory analysis, we propose that CD8 TEM preferentially differentiate into clonally-expanded PD1- CD45RA+ effector-memory CD8+ T cells (CD8 TEMRA) with pronounced cytotoxicity. In contrast, in non-responders, CD8 TEM remain frozen in their effector-memory state. Finally, in responders, CD8 TEMRA display a high degree of T cell receptor sharing with blood, consistent with their patrolling activity. These findings may help understand the possible mechanisms underlying response to atezo/bev in aHCC.

Poor Efficacy of Immune Checkpoint Inhibitors Plus Chemotherapy in Lung Cancer Patients with EGFR/ERBB2 Exon 20 Insertion.

EGFR and ERBB2 exon 20 insertion (Ex20ins) account for a small fraction of patients with EGFR mutations. The efficacy of immune checkpoint inhibitors (ICIs) for these patients was still controversial. This retrospective study enrolled lung cancer patients harboring either EGFR or ERBB2 Ex20ins mutations. All the patients were treated with platinum-based chemotherapy plus ICIs, or platinum-based chemotherapy. The demographic features and clinical outcome of each patient were reviewed and analyzed. When treated with immunochemotherapy, patients with EGFR/ERBB2 Ex20ins mutations (n = 31) had poor PFS compared with those without EGFR mutations (n = 141, 5.0 mon and 11.2 mon, p < 0.001). When compared with those with EGFR classic mutations who received immunotherapy as the salvage therapy (n = 24), these patients with EGFR/ERBB2 Ex20ins mutations had similar PFS (5.0 mon and 4.1 mon, p = 0.625), ORR (37.5% vs. 48.4%), and DCR (70.8% vs. 77.4%). In the patients with EGFR/ERBB2 Ex20ins mutations, the PFS of those treated with chemotherapy (n = 54) and those treated with immunochemotherapy (n = 31) was 6.5 mon vs. 5.0 mon (p = 0.066). In the EGFR Ex20ins subgroup, the PFS of addition of bevacizumab to chemotherapy (n = 20) and chemotherapy alone (n = 16) was 8.8 mon and 5.2 mon, respectively (p = 0.082) or immunochemotherapy (n = 15, 8.8 mon and 5.0 mon, p = 0.097). Similarly, in the ERBB2 subgroup, the combination of bevacizumab and chemotherapy achieved a numerically longer PFS over chemotherapy alone (9.1 mon and 4.5 mon, p = 0.253), but there was no statistical significance. This study showed that platinum-based chemotherapy plus ICIs had limited efficiency compared to platinum-based chemotherapy for patients with EGFR/ERBB2 Ex20ins. Chemotherapy plus bevacizumab may be a potential scheme for these patients.

DDEL-02. CLINICAL BENEFIT OF BEVACIZUMAB AND IRINOTECAN (BEV+IRI) IN PATIENTS WITH RELAPSED/REFRACTORY GLIOBLASTOMA (R/RGBM) AND ITS POTENTIAL PREDICTORS

Abstract BACKGROUND/AIM: Bevacizumab-containing chemotherapy constitutes an important salvage treatment for recurrent/refractory glioblastoma(r/rGBM). Patients and methods: We retrospectively collected the data of r/rGBM patients treated with the combination of bevacizumab and irinotecan (BEV+IRI) as their salvage treatment from July 2013 and December 2021 in Konkuk Medical Center of Korea. Patients with available results from molecular diagnostic tests were eligible, and markers of interest were examined including the presence of MGMT methylation, IDH1/2 mutation, or 1p/19q co-deletion. Efficacy of BEV+IRI and its potential biomarker was explored. RESULTS: Among 21 patients, 38.1% demonstrated European Cooperative Oncology Group-Performance scale (ECOG-PS) ≥3. The majority (71.4%) received BEV+IRI as their second-line chemotherapies, and the median dose was 5 (range=1-25). Objective response rate (ORR) was 33.3% and disease-control rate (DCR) was 85.7%. Irrespective of objective response, early clinical response was achieved in 14(66.7%) patients. During the median follow-up of 16.4 months for survivors, median progression-free survival (PFS) and overall survival (OS) were 3.6 and 6.8 months, respectively. ECOG PS≥3 and TP53 loss were independent predictors of an unfavorable OS, while prompt clinical improvement could predict favorable OS. Any molecular aberration was associated with OS or PFS in the study. CONCLUSION: Salvage BEV+IRI treatment in r/rGBM conferred comparable clinical benefit. ECOG PS ≥3, TP53 loss, and lack of prompt clinical improvement after the treatment were significantly associated with an unfavorable OS.