Efficacy Of Atezolizumab Research Articles

Efficacy of Atezolizumab in Subsequent Lines of Therapy for NSCLC Patients: Insights from Real-World Data.

This retrospective study involved 147 advanced NSCLC patients treated with atezolizumab following progression on prior platinum-based chemotherapy at two academic centers in Serbia. Data on demographics and clinical, pathological, and molecular characteristics were collected. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards regression identified outcome predictors. The median PFS was 7.13 months, and median OS was 38.6 months. The overall response rate (ORR) was 15%, with a disease control rate (DCR) of 57.9%. No significant PFS differences were observed between patients treated with atezolizumab in the second line versus later lines. Patients with good performance status (ECOG 0-1) had significantly better PFS compared to those with poorer status (12.03 vs. 1.63 months, p < 0.0001). Atezolizumab is effective in both second-line and later-line settings for advanced NSCLC, particularly in patients with good performance status. This highlights the importance of patient selection based on performance status, as well as the need for wider access to ICIs in resource-limited regions.

Extracellular Vesicles May Predict Response to Atezolizumab Plus Bevacizumab in Patients with Advanced Hepatocellular Carcinoma.

Treatment with atezolizumab and bevacizumab has been approved as one of the standards of care for patients with advanced hepatocellular carcinoma (HCC). The median overall survival (OS) upon available treatments still remains below 2 years, urgently suggesting better stratification tools to identify ideal candidates for this treatment and potentially allowing personalized approaches. In this study, we evaluated the potential role of extracellular vesicles (EVs) as a novel biomarker in patients receiving atezolizumab and bevacizumab for HCC. We characterized EVs in 212 longitudinal serum samples from an observational cohort of 53 individuals with advanced HCC, who started therapy with atezolizumab plus bevacizumab at our center between January 2020 and March 2022. In our cohort, the overall efficacy of atezolizumab and bevacizumab was comparable to previously published phase III data. We detected significantly smaller EVs in treatment responders, while enlarged EVs were associated with significantly decreased efficacy of atezolizumab and bevacizumab in terms of OS. A decrease in vesicle size during immunotherapy was related to a longer progression-free survival (PFS). A univariate Cox regression analysis including various clinicopathological parameters (e.g., tumor stage, markers of inflammation, organ dysfunction, or tumor markers) revealed vesicle size as an independent prognostic marker in HCC patients receiving atezolizumab and bevacizumab. Moreover, higher vesicle concentrations and lower zeta potentials were identified as a positive prognostic factor throughout treatment. Distinct EV characteristics such as vesicle size, concentration, and zeta potential represent promising novel biomarkers in patients with advanced HCC receiving atezolizumab and bevacizumab, potentially helping to identify optimal candidates for checkpoint inhibitor-based treatments.

P47-1 The safety and efficacy of atezolizumab in small cell lung cancer: a systematic review

P47-1 The safety and efficacy of atezolizumab in small cell lung cancer: a systematic review

Cannabidiol enhances Atezolizumab efficacy by upregulating PD-L1 expression via the cGAS-STING pathway in triple-negative breast cancer cells.

The treatment of patients with triple negative breast cancer (TNBC) relies on cytotoxic therapy. Currently, atezolizumab and chemotherapy can be combined in patients with TNBC. However, this approach is not effective for all patients with low reactivity to atezolizumab. As there is a lack of alternative treatment options, new anti-cancer drugs are urgently needed to enhance atezolizumab reactivity against TNBC. Recent strategies have focused on regulating the expression of programmed death-ligand 1 (PD-L1) or enhancing immune response activation by combining anti-cancer drugs with immune checkpoint inhibitors (ICIs). Cannabidiol (CBD), a cannabinoid component derived from the cannabis plant, has been reported to have anti-cancer therapeutic potential because of its capacity to induce apoptotic cell death in tumor cells while avoiding cytotoxicity in normal cells. Previous studies have demonstrated the effects of CBD on apoptosis in various cancer cell types. However, the potential role of CBD as an immune modulator in the regulation of PD-L1 expression and anti-cancer immune responses remains to be explored. In this study, we found that CBD stimulated PD-L1 expression in TNBC cells, which significantly induced the CBD-mediated cGAS-STING pathway activation. Taken together, we demonstrated that the combination of CBD and anti-PD-L1 antibody enhances the anti-cancer immune response in vitro and in vivo experiments. Our findings identified the mechanism of PD-L1 regulation by CBD in TNBC cells and suggested that CBD could be a potential candidate for the development of new combinatorial strategies with ICIs in TNBC patients.

955P Association of skeletal muscle mass with safety and efficacy of atezolizumab (atezo) plus bevacizumab (bev) in Japanese patients (pts) with unresectable hepatocellular carcinoma (uHCC): Results from the ELIXIR study

955P Association of skeletal muscle mass with safety and efficacy of atezolizumab (atezo) plus bevacizumab (bev) in Japanese patients (pts) with unresectable hepatocellular carcinoma (uHCC): Results from the ELIXIR study

954P Evaluation of antigen-specific CD8 T cell responses to predict efficacy of atezolizumab and bevacizumab treatment in hepatocellular carcinoma

954P Evaluation of antigen-specific CD8 T cell responses to predict efficacy of atezolizumab and bevacizumab treatment in hepatocellular carcinoma

The Association of Immune-Related Adverse Events with the Efficacy of Atezolizumab in Previously Treated Advanced Non-Small-Cell Lung Cancer Patients: A Single-Center Experience.

Immune checkpoint inhibitors (ICIs) are pivotal in managing metastatic non-oncogene addicted non-small-cell lung cancer (NSCLC). They have unique toxicities known as immune-related adverse events (irAEs). Previous studies have linked irAEs during atezolizumab-based first-line treatments in advanced NSCLC with improved outcomes. This study explored the association between irAEs and the efficacy of atezolizumab in advanced NSCLC patients who had previously received platinum-based chemotherapy. The study involved 105 advanced NSCLC patients who received atezolizumab monotherapy after progressing on at least one line of platinum-based chemotherapy from a single academic institution in Serbia. Data were obtained from a hospital lung cancer registry. Among the participants, 63.8% were male, with the majority being current (53.3%) or former smokers (37.1%). About half had a good performance status (ECOG PS 0-1) at the start of atezolizumab treatment. irAEs occurred in 23 patients (21.9%). The median progression-free survival (mPFS) was significantly longer for patients with irAEs (13.03 months) compared to those without (3.4 months) (HR 0.365 [95% CI, 0.195-0.681], p = 0.002). irAEs and ECOG PS 0-1 were predictors of longer mPFS, with irAEs being more common in patients with good performance status (p = 0.01). irAEs were linked to improved mPFS in NSCLC patients treated with atezolizumab after multiple lines of platinum-based chemotherapy.

Abscopal effect in a patient with advanced hepatocellular carcinoma upon resuming bevacizumab in combination with atezolizumab after radiotherapy.

Combining bevacizumab with atezolizumab enhances the antitumor effects of the treatment by activating an immune response. This combination is approved for the treatment of unresectable hepatocellular carcinoma (HCC). An abscopal effect is associated with an immune response triggered by radiation-induced immunogenic cell death, based on experimental models. Thus, combining radiotherapy and immunotherapy is expected to induce an abscopal effect. However, the clinical significance of immunotherapy in the abscopal effect remains unknown due to the rarity of clinical cases. Herein, we report a case of advanced HCC with lung and adrenal metastases. The antitumor efficacy of atezolizumab and bevacizumab (atezo/bev) was enhanced following stereotactic body radiotherapy (SBRT), although atezo/bev did not yield a sufficient therapeutic response pre-SBRT. Furthermore, an abscopal effect following SBRT was not observed during atezolizumab alone but was evoked after resuming bevacizumab in combination with atezolizumab, culminating in the patient achieving a complete response status. These findings suggest that immune activation following radiotherapy may be related to the induction of an abscopal effect in clinical practice as well as in experimental settings, and combining immunotherapy with bevacizumab post-radiotherapy could evoke an abscopal effect in a case of HCC, even though immune checkpoint inhibitor use alone may be insufficient.

Atezolizumab combined with immunogenic salvage chemoimmunotherapy in patients with transformed diffuse large B-cell lymphoma.

Patients with relapsed/refractory (R/R) transformed diffuse large B-cell lymphoma (DLBCL) from indolent B-cell lymphomas, including Richter transformation (RT), have a poor prognosis. PD-1/PD-L1 antibodies produce modest objective and complete response rates (ORR and CRR) in B-NHL as monotherapy but may synergize with immunogenic chemotherapies like gemcitabine and oxaliplatin (GemOx). Thus, we evaluated the safety and efficacy of atezolizumab plus rituximab and GemOx (R-GemOx+Atezo) in R/R transformed DLBCL, including RT. We conducted a phase I trial including patients with transformed DLBCL after ≥1 prior therapy. Patients received up to 4 cycles of R-GemOx-+Atezo. Patients in CR could then proceed to Ratezo maintenance until progression. A safety lead-in with dose-limiting toxicity (DLT) evaluation was enrolled to confirm the recommended phase 2 dose (RP2D), followed by 2 expansion cohorts: one for transformed follicular lymphoma (FL) and another for non-FL transformed DLBCL, including RT. Twenty-seven patients were enrolled. One of the 6 safety lead-in patients had a DLT attributed to atezolizumab, a grade 4 Stevens-Johnson syndrome (SJS). The most common grade ≥3 events were neutropenia (18.5%), lymphopenia (18.5%), and thrombocytopenia (14.8%). The overall and complete response rates (ORR and CRR) were 59% and 33%, respectively. The ORR and CRR in transformed FL were 79% and 43%, and 38% and 23% in transformed non-FL, respectively. The median PFS and OS of the total population were 4.2 and 7.7 months, respectively. R-GemOx+Atezo was well tolerated and demonstrated promising preliminary efficacy in patients with R/R transformed DLBCL.

Analysis of Factors Predicting the Real-World Efficacy of Atezolizumab and Bevacizumab in Patients with Advanced Hepatocellular Carcinoma.

Atezolizumab and bevacizumab have shown promising results for the treatment of advanced hepatocellular carcinoma (HCC) in clinical trials. In this study, the real-world efficacy and safety of atezolizumab and bevacizumab in treating advanced HCC were evaluated. In this retrospective study of patients at a Korean tertiary cancer center, 111 patients with Barcelona Clinic Liver Cancer stage B or C HCC received atezolizumab and bevacizumab as first-line therapy from May 2022 to June 2023. We assessed the progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and adverse events. Patients with Barcelona Clinic Liver Cancer stage C HCC and Child-Pugh class A liver function were included in the study. The median PFS was 6.5 months, with an ORR of 27% and a DCR of 63%. Several factors, including the albumin-bilirubin grade, age, C-reactive protein and α-fetoprotein in immunotherapy score, macrovascular invasion, lung metastases, and combined radiotherapy, were found to significantly influence PFS (p<0.05). Patients with peritoneal seeding showed an higher ORR. The safety profile was consistent with that observed in clinical trials. Atezolizumab and bevacizumab demonstrated real-world efficacy in the treatment of advanced HCC, with ORRs and DCRs aligning with those observed in clinical trials. Variations in PFS and ORR based on specific risk factors highlight the potential of atezolizumab and bevacizumab in precision medicine for advanced HCC.

Safety/efficacy of atezolizumab + bevacizumab during anti-platelet/anticoagulation therapy in unresectable hepatocellular carcinoma.

This study aimed to determine the safety and efficacy of atezolizumab + bevacizumab therapy in hepatocellular carcinoma patients receiving anti-platelet agents or anticoagulants. Patients were divided into those using (IM out) and those not using (IM in) anti-platelet agents or anticoagulants, who violated the exclusion criteria of the IMbrave150 trial, and were retrospectively examined. The study included 185 patients (IM in: 157; IM out: 28). For first-line treatment, progression-free survival was 184 days for IM in and 266 days for IM out (p = .136). Overall survival was 603 days for IM in and not reached for IM out (p = .265), with no significant between-group difference. Similarly, there were no significant between-group differences in progression-free survival or overall survival for later-line treatment. Haemorrhagic adverse events of ≥grade 3 were observed in 11 IM in patients and 3 IM out patients. No significant factors associated with haemorrhagic adverse events of ≥grade 3 were identified in the multivariate analysis including IM out classification, whose p value was .547. Regarding thrombotic/embolic adverse events in the IM out group, one case of exacerbation of portal vein thrombosis was observed. No deaths were directly attributable to bleeding events or exacerbations of thrombosis. Atezolizumab + bevacizumab therapy shows similar safety and efficacy in patients receiving and those not receiving anti-platelet agents or anticoagulants; therefore, it can be considered for patients with hepatocellular carcinoma receiving anti-platelet agents or anticoagulants.

The efficacy of atezolizumab plus bevacizumab in the treatment of unresectable hepatocellular carcinoma in cirrhotic and non-cirrhotic patients.

e16214 Background: The IMbrave150 trial established that the combination of atezolizumab plus bevacizumab (AB) confers a significant progression-free survival (PFS) benefit when compared with sorafenib in patients with unresectable hepatocellular carcinoma (HCC). However, the nuanced impact of cirrhotic status on treatment response was not established by the study, leaving a critical aspect of patient stratification and outcomes yet to be fully understood. Methods: We conducted a retrospective single-center study of patients with HCC treated with AB between 2020 and 2023. Eligible patients were those who underwent at least one cycle of AB and had a follow-up period of at least three months post-AB initiation. Independent samples T-test and X2 and Fisher’s exact tests were used to evaluate associations between variables. PFS was calculated using the Kaplan-Meier method and compared according to cirrhotic status using the log-rank test. A Cox regression analysis was performed to estimate survival hazard ratios (HR). Results: Among 28 patients, the mean age at diagnosis was 64 years (SD 11), 18 (64%) were male, 26 (93%) had Child-Pugh (CP) class A liver function, and 18 (64%) were cirrhotic. Most patients presented with Barcelona Clinic Liver Cancer stage C disease (61%) and received AB in the first-line setting (93%). Clinicopathological features according to cirrhotic status are detailed in Table 1. With a median follow-up of 14 months (95% CI 8-20) since AB initiation, 16 progression events were recorded, resulting in a median PFS of 12 months (95%CI 6-18) for the entire cohort. Univariate analysis revealed an inferior median PFS in patients with cirrhotic HCC (7 months [95%CI 5-9] vs. not reached [p = 0.038]). However, in a multivariate Cox analysis, only obesity emerged as a significant predictor of an inferior PFS (HR 4.6; 95% CI 1.3 - 16.0, p = 0.018). Conclusions: In our study, cirrhosis was not associated with an inferior PFS. Notably, the majority of cirrhotic patients in this cohort exhibited CP A liver function, so uncertainties persist regarding the impact of cirrhosis on cancer progression in patients with CP B and C liver function. Further investigation is warranted to comprehensively evaluate whether cirrhotic, non-cirrhotic, and obese subgroups respond differently to AB therapy. [Table: see text]

A randomized phase II trial of atezolizumab with or without tiragolumab before and after definitive chemoradiation for unresectable stage III non-small cell lung cancer (NSCLC; AFT-57).

TPS8123 Background: A minority of patients with unresectable stage III non-small cell lung cancer (NSCLC) may be cured by chemoradiotherapy (CRT). Adjuvant checkpoint inhibition through PD-L1 blockade after CRT improved survival compared to placebo in the PACIFIC trial (median progression-free survival (mPFS) 16.9 vs 5.6 months (mo), median overall survival (mOS) 47.5 vs 29.1 mo), but overall survival at 5 years remains below 50% (Spigel D, et al J Clin Oncol 2022, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9015199/ . Only patients completing CRT without progression and with good performance status were eligible for this approach. Neoadjuvant checkpoint inhibition would allow more patients the opportunity to benefit from immunotherapy and may attenuate tumor-related immunosuppression via depletion of regulatory T cells and clonal expansion of effector T cells, thereby improving tumor immunogenicity. Neoadjuvant atezolizumab had favorable outcomes compared to historic PACIFIC data in the phase II single arm trial, AFT-16 (mPFS 30 mo and mOS not reached). Whether combination immunotherapy therapy before CRT will improve outcomes in this setting is the question posed in the AFT-57 trial. Methods: This phase II randomized Alliance Foundation Trials study (AFT-57) will evaluate safety and efficacy of atezolizumab with or without the anti-TIGIT monoclonal antibody, tiragolumab, before and after definitive CRT with concurrent atezolizumab. The primary endpoint is PFS in the two experimental arms with a goal to select the most promising regimen for further study. AFT-57 will randomly assign 158 patients with stage III NSCLC (AJCC v8), Eastern Cooperative Oncology Group performance status 0-1, no active autoimmune disease and no underlying organ dysfunction to 2 cycles of neoadjuvant atezolizumab (1200 mg intravenously [IV] every 21 days) with or without tiragolumab (600 mg IV). Non-progressing patients will receive carboplatin and paclitaxel weekly with atezolizumab 1200 mg IV every 21 days concurrent with 60 Gray involved field thoracic radiation in 30 daily fractions (Monday - Friday) followed by atezolizumab with or without tiragolumab on the same schedule as the neoadjuvant doses, with a plan to complete one year of therapy. A pilot cohort of 20 patients for whom tiragolumab will be combined with atezolizumab during chemoradiotherapy is planned toward the end of accrual. Correlative science includes tissue and blood-based immune-related biomarkers at baseline and during therapy. This trial utilizes the Alliance Participant Engagement Portal, a patient-facing site designed to provide information and resources to Alliance clinical trial participants. The trial was activated on 12/7/23 with the first patient screened 1/19/24. Clinical trial information: NCT05798663 .

201P Retrospective multicenter real-life study evaluating the efficacy of atezolizumab in combination with bevacizumab in metastatic hepatocellular carcinoma: HIREAL study

201P Retrospective multicenter real-life study evaluating the efficacy of atezolizumab in combination with bevacizumab in metastatic hepatocellular carcinoma: HIREAL study

Cobimetinib plus atezolizumab for RAS and NF1/2-mutated poorly differentiated thyroid carcinoma.

6106 Background: Poorly differentiated thyroid carcinomas (PDTC) are a subset of thyroid cancers characterized by high-grade pathologic features. They hold an intermediate position on the spectrum of follicular-derived thyroid cancers. Due to their more aggressive clinical behavior, PDTCs typically exhibit shorter responses to the usual kinase inhibitors (KIs) used in advanced differentiated thyroid cancers and develop resistance earlier on. In fact, median progression free survival (PFS) with single-agent lenvatinib in patients with PDTC in the SELECT trial (n=28) was 14.8 months. Although there are increasing data to support the use of immunotherapy plus KI combinations in anaplastic thyroid cancer, evidence demonstrating the efficacy of this strategy in PDTC is sparse. We aimed to study the safety and efficacy of atezolizumab combined with KIs in PDTC. Methods: We enrolledpatientswith PDTC in a single-center phase II prospective trial of atezolizumab plus mutation-determined targeted therapy (NCT03181100). Patients with RAS or NF- mutated tumors were treated with atezolizumab plus the MEK inhibitor (MEKi) cobimetinib. Primary outcome was median overall survival (mOS). Best response to therapy was assessed per RECIST v1.1; survival by the Kaplan-Meier method. Results: Eight patients with RAS/NF-mutated PDTC were enrolled. Median age at treatment start was 68.5 years. All patients had distant metastatic disease at time of enrollment. Prior to study entrance, 7/8 patients (88%) had surgical resection of the primary tumor, 6/8 (75%) radioactive iodine, 2/8 (25%) external beam radiation to the neck, and 3/8 (38%) bridging cytotoxic chemotherapy. All patients were naïve to KIs. Six (75%) patients had RAS mutations (1 HRAS, 3 KRAS, 2 NRAS) and 3 (38%) had NF mutations (2 NF1, 1 NF2). One patient’s tumor harbored both KRAS and NF2 mutations at baseline. PD-L1 score was positive in 3/4 evaluable specimens. Median duration of follow-up was 65 months. Best response to therapy was stable disease in 6/8 (75%), partial response in 1/8 (12.5%) and progressive disease in 1/8 (12.5%). mOS was 23 months (95% CI, 12.8 – 33.2) and median PFS was 7 months (95% CI, 2.4 – 11.6). 4/8 patients received radioactive iodine (RAI) while on systemic therapy. Median dose of RAI was 149 millicuries (range, 108 – 153). mOS was significantly longer in patients who received RAI (32 vs 16 months; p= 0.034). The combination of cobimetinib + atezolizumab was overall well tolerated, with an expected adverse event profile. Conclusions: In patients with metastatic PDTC driven by RAS or NFmutations, combination of the anti-PD-L1 atezolizumab with MEKi cobimetinib showed some clinical efficacy, although PFS was shorter than with single-agent lenvatinib. However, SELECT trial did not delineate responses by driver mutations. This combination could thus be considered in selected patients at high risk of complications with antiangiogenic KIs. Clinical trial information: NCT03181100 .

Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway

The mitotic MTH1 inhibitor TH1579 is a dual inhibitor that inhibits mitosis and incorporation of oxidative DNA damage and leads to cancer-specific cell death. The response to immune checkpoint inhibitor (ICI) treatment is often augmented by DNA damaging agents through the cGAS-STING pathway. This study investigates whether TH1579 can improve the efficacy of immune checkpoint blockades through its immunomodulatory properties. Various human and murine cancer cell lines were treated with mitotic MTH1i TH1579, and the expression of PD-L1 and T-cell infiltration-related chemokines was analysed by flow cytometry and real-time qPCR. Syngeneic mouse models were established to examine the combined effect of TH1579 and PD-L1 blockade. In our investigation, we found that TH1579 upregulates PD-L1 expression at both the protein and mRNA levels in human cancer cell lines. However, in murine cell lines, the increase was less pronounced. An in vivo experiment in a syngeneic mouse melanoma model showed that TH1579 treatment significantly increased the efficacy of atezolizumab, an anti-PD-L1 antibody, compared to vehicle or atezolizumab monotherapy. Furthermore, TH1579 exhibited immune-modulatory properties, elevating cytokines such as IFN-β and chemokines including CCL5 and CXCL10, in a cGAS-STING pathway-dependent manner. In conclusion, TH1579 has the potential to improve ICI treatment by modulating immune checkpoint-related proteins and pathways.

Abstract PO3-17-12: Safety and efficacy of Atezolizumab in combination with nab-Paclitaxel in patients with PD-L1 positive metastatic or locally advanced triple-negative breast cancer: A pan-UK cancer centre experience

Abstract BACKGROUND Within the United Kingdom (UK), combination chemo-immunotherapy with Atezolizumab and nab-Paclitaxel is National Institute for Health and Care Excellence (NICE) approved as a first line palliative systemic treatment option for patients with advanced triple-negative breast cancer (aTNBC) with programmed death-ligand 1 (PD-L1) expression ≥1%. Trials demonstrated progression-free survival (PFS) and overall survival (OS) benefits. Treatment-related toxicities may impact on quality of life and result in treatment delay or discontinuation. We conducted a National Service Evaluation (SE) to assess the safety and efficacy in a “real-world” dataset. METHODS Data from patients with aTNBC who received Atezolizumab/nab-Paclitaxel between 9th March 2019 and 2022 across 10 UK Cancer Centres were analysed. All grade 1-4 toxicities were recorded in accordance with Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 scoring system. Participation was contingent on local approval for this project, and data transferred following receipt of a data sharing agreement. Kaplan-Meier curves for PFS and OS were calculated. RESULTS 129 patients were included in the analysis with a median age of 55 (30-82). 42.6% (n=55) had a PS of 0, 51.2% (n=66) a PS of 1 and 3.9% (n=5) had a PS of 2. Atezolizumab/nab-Paclitaxel was given in the first line setting in most patients (84.5%, n= 109), but in 15.5% (n=20) in the second line setting (privately insured). 21.7% (n=28) of patients presented with de novo metastatic disease, 58.1% (n=75) of patients were post-menopausal and 6.2% (n=8) had a BRCA1 or 2 mutation. 76.7% of patients (n=99) had previous neo-/adjuvant treatment in the non-metastatic setting: 55.8% had prior treatment with a taxane, 51.2% anthracycline, 22.5% platinum, and 66.7% had prior radiotherapy. 83.7% (n= 108) had invasive ductal breast cancer, and 84.5% (n=109) presented with 0-3 number of metastatic sites with 15.5% (n=20) having ≥ 4 metastatic sites. Here, the nodal metastatic site dominated in 78.3% of patients. Grade ≥ 3 events occurred in 21.7% (n=28) of patients. These were decreased neutrophil count (10.1%, n=13), pyrexia (2.3%, n=3), diarrhoea (1.6%, n=2), hypothyroidism (1.6%, n=2), peripheral neuropathy (1.6%, n=2), anaemia (1.6%, n=2), GGT rise (0.8%, n=1), fatigue (0.8%, n=1), hypophysitis (0.8%, n=1), pneumonitis (0.8%, n=1), nausea (0.8%, n=1), mucositis (0.8%, n=1), platelet count decreased (0.8%, n=1), infections (0.8%, n=1). Increased rates of Grade ≥ 3 colitis (2.3%, n=3) and hepatitis (3%, n=2.3) were observed. 20.2% (n=26) of patients required steroids to treat toxicities. Reason for treatment discontinuation included in 58.1% (n=75) disease progression, and 7.8% (n=10) unacceptable toxicity. In 22.5% of patients’ treatment was still ongoing at time of data lock. At approximately 12 weeks, 7.8% of patients had a complete and 51.2% a partial response, 10.1% had stable and 22.5% progressive disease and for 8.5% the response was not known as they have not yet reached 12 weeks since treatment start. Median PFS was 5 months and OS was 14 months. CONCLUSIONS The toxicity profile of Atezolizumab/nab-Paclitaxel was comparable to literature, however, both PFS and OS were shorter. In comparison to the IMpassion130 trial data, patients within this national SE project were less fit and more heavily pre-treated. A higher number of any grade hyperthyroidism and fatigue, and of grade ≥ 3 colitis and hepatitis were noticed. Baseline patient characteristics XX- XX Citation Format: Jasmin V Waterhouse, Alexandra Holdich, Florentia Mina, Mariam Obeid, Kroopa Joshi, Sophie Barrett, Lavarniya Rajakumar, Gemma McCormick, Sally Seymour, Panagiotis Koliou, Rushan Sylva, Olubukola Ayodele, Ashram Gautam, Jenny Smith, Jenny McKeon, Thomas Strawson-Smith, Rosalie Douglas, Annabel Borley, Apostolos Konstantis, Sophie McGrath. Safety and efficacy of Atezolizumab in combination with nab-Paclitaxel in patients with PD-L1 positive metastatic or locally advanced triple-negative breast cancer: A pan-UK cancer centre experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-17-12.

Abstract PO4-13-09: Paclitaxel affects the efficacy of PD-1 blockade by interfering with lipid metabolism reprogramming in patients with breast cancer

Abstract Background: The question of how chemotherapeutic drugs affect the efficacy of PD-1/PD-L1 antibodies in patients with breast cancer is still pending. In a previously single-cell sequencing study, we have demonstrated that paclitaxel reduces the level of CXCL13+ T cells and other immune cells critical for atezolizumab to work, leading to inferior efficacy of atezolizumab in triple negative breast cancer (TNBC). How paclitaxel affects these important immune cells remains obscure. Recently, plasma metabolomic and proteomics analysis have shown that patients’ systemic metabolic signatures is correlated with the response of PD-1/PD-L1 antibody. As such, understanding the differential metabolic influences of the diverse chemotherapeutic drugs that comprise an immune response to TNBC offers an opportunity to appropriately select chemotherapeutic backbones for ICIs. Methods: We collected pre- and post-treatment plasma samples from breast cancer patients for metabolomic and proteomic analysis, including four patient cohorts: two independent cohorts (discovery cohort and validation cohort) in which patients were treated with ICIs, one cohort in which patients were treated with paclitaxel, and one cohort of patients treated with nab-paclitaxel. Patients were divided into responder group (R, tumor shrinkage) or non-responder group (NR, tumor increase) according to the change in tumor size after treatment relative to baseline. This was followed by integrating metabolomics and proteomics with single-cell transcriptome, along with in vitro experiments, to shed light on the mechanisms of action leading to ICIs resistance in breast cancer patients. Results: In the discovery cohort, the metabolites that mostly differed between the R and NR groups at baseline were lysoglycerophospholipids. These results were further validated in the validation cohort of patients. The dynamic changes of lysoglycerophospholipids were still significantly different between the R and the NR groups after ICIs treatment in the discovery cohort. It’s worth noting that the level of lysophosphatidylcholines (LPCs), the most prominent lysoglycerophospholipids, increased significantly in the R group, while no significant changes among LPCs were found in the NR group after ICIs treatment. In the validation cohort, the median PFS of LPClow patients was 1.8 months versus 6.8 months in the LPChigh group (P = 0.0068). After one cycle of paclitaxel treatment, the metabolic status of patients changed dramatically, especially the levels of lipids. It is notable that most LPCs were significantly downregulated after paclitaxel treatment. However, in patients who received nab-paclitaxel, few significantly changed lipids were detected after one cycle nab-paclitaxel treatment compared with their baseline conditions. Interestingly, the levels of LPCs were upregulated after one cycle nab-paclitaxel treatment, but decreased after paclitaxel treatment. Single-cell omics results showed that in patients' PBMCs, CXCR4+ NK cells were the most closely related to plasma LPC levels, while FGFBP2+ NK cells were in the tumor microenvironment. We isolated and expanded NK cells from PBMCs for in vitro experiments, and found that LPC stimulation can significantly upregulate the expression of CXCR4+ in NK cells, and further increase the chemotaxis and cytotoxicity of NK cells. Conclusions: In breast cancer patients receiving ICIs, the systemic lipid metabolism status, especially lysoglycerophospholipids, is closely related to the efficacy of immunotherapy. The key molecule LPC, the most prominent lysoglycerophospholipids, may promote the efficacy of immunotherapy by activating NK cells in breast cancer patients. Paclitaxel may impair the efficacy of immunotherapy by affecting the systemic lipid metabolism status, especially by reducing plasma LPC levels, so it is not a suitable partner for ICIs. Citation Format: Hongnan Mo, Jiashu Han, Jingtong Zhai, Xiaoying Sun, Xiuwen Guan, Haili Qian, Fei Ma. Paclitaxel affects the efficacy of PD-1 blockade by interfering with lipid metabolism reprogramming in patients with breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-13-09.

Usefulness of atezolizumab plus bevacizumab as second-line therapy for patients with unresectable hepatocellular carcinoma.

To clarify the efficacy of atezolizumab (ATZ) plus bevacizumab (BEV) as the second-line therapy for patients with unresectable hepatocellular carcinoma (HCC). The subjects were 82 patients with HCC receiving ATZ/BEV, including 33 patients with previous therapies with molecular-targeted agents (MTA). Therapeutic efficacy was evaluated using contrast-enhanced CT according to the mRECIST. The Child-Pugh scores were 5, 6,7 and 8 in 40, 35, 5 and 2 patients, respectively, and the extents of HCC progression were BCLC stage A, B and C in 3, 31 and 48 patients, respectively. Early therapeutic efficacy was evaluated in 67 patients, and percentages of patients achieving CR/PR/SD/PD until 12 weeks were 3.0%/29.9%/49.3%/17.9%, respectively, indicating ORR of 32.8% and DCR of 82.1%, The ORR was higher in MTA-naïve patients (40.5%) than in those after discontinuation of lenvatinib due to PD (7.7%, P = 0.0410), while the DCR was equivalent between both patients (83.3% vs 80.0%, P = 0.1184), and the multivariate analysis revealed previous MTA therapies with lenvatinib alone as a factor to deteriorate the ORR (HR of 4.846 (P = 0.0619)). The OS rates at 24 and 48 weeks were 86% and 72%, respectively, and the rates did not differ between MTA-naïve and MTA-experienced patients. Multivariate analyses revealed that achievement of CR, PR or SD and peripheral neutrophil/lymphocyte ratio were associated with a favorable outcome (HR of 0.124, P<0.0001 and 0.351, P = 0.0303). ATZ/BEV merits consideration even for MTA-experienced patients, since the OS was equivalent to those in MTA-naïve patients despite of an unfavorable early therapeutic efficacy.

Intestinal Microbiome Associated with Efficacy of Atezolizumab and Bevacizumab Therapy for Hepatocellular Carcinoma.

The combination of atezolizumab and bevacizumab has become the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). However, no studies have reported on specific intestinal microbiota associated with the efficacy of atezolizumab and bevacizumab. In this study, we analyzed fecal samples collected before treatment to investigate the relationship between the intestinal microbiome and the efficacy of atezolizumab and bevacizumab. A total of 37 patients with advanced HCC who were treated with atezolizumab and bevacizumab were enrolled. Fecal samples were collected from the patients, and they were divided into responder (n = 28) and non-responder (n = 9) groups. We compared the intestinal microbiota of the two groups and analyzed the intestinal bacteria associated with prognosis using QIIME2. The alpha and beta diversities were not significantly different between both groups, and the proportion of microbiota was similar. The relative abundance of Bacteroides stercoris and Parabacteroides merdae was higher in the responder group than in the non-responder group. When the prognosis was analyzed by the presence or absence of those bacteria, patients without both had a significantly poorer prognosis. Differences in intestinal microbiome are involved in the therapeutic effect of atezolizumab and bevacizumab.