Efficacy and safety of PARPis combined with an ICIs for advanced or metastatic triple-negative breast cancer: a single-arm meta-analysis.

Although the intervention for triple-negative breast cancer (TNBC) patients has improved and survival time has increased, the combination of immune checkpoint inhibitors(ICIs) and PARP inhibitors (Poly ADP-Ribose Polymerase inhibitors, PARPis) is still controversial. Previous studies revealed that the combined use of ICIs and PARPis led to increased antitumor activity. However, most of these combined regimens are nonrandomized controlled trials with small sample sizes. The purpose of this meta-analysis was to evaluate the efficacy and safety of ICIs combined with PARPis in patients with advanced or metastatic TNBC. The PubMed, Embase, Cochrane Library and Web of Science databases were systematically searched. The results including the objective remission rate (ORR), disease control rate (DCR), progression-free survival (PFS) and adverse events (AEs), were subjected to further analysis. Four studies involving 110 subjects were included in this meta-analysis. The combined ORR and DCR were 23.6% and 53.6%, respectively; while the ORR and DCR of BRCAmut patients were 38.1% and 71.4%, respectively. The median PFS of the patients was 4.29 months. As for safety, the most common AEs were nausea (49.0%), anemia (44.3%) and fatigue (40.6%). Most of them were grade 1 or 2, and the incidence of adverse events ≥ III was obviously low. Except for anemia, the incidence of AEs ≥ III was < 10%. This meta-analysis revealed that the combination of ICIs and PARPis has good efficacy and safety for advanced or metastatic TNBC patients.

Prognostic assessment of 18F-boronophenylalanine positron emission tomography (BPA-PET) in salvage boron neutron capture therapy for malignant brain tumors.

Background: Boron neutron capture therapy (BNCT) stands out as a propitious anti-cancer modality. 18F-boronophenylalanine positron emission tomography (BPA-PET) holds the potential to ascertain the concentration of BPA within the tumor, enabling meticulous treatment planning and outcome evaluation. However, no studies have been conducted on comparing the outcomes of those treated with BNCT to those who did not undergo this therapy. This study endeavors to analyze the correlation between BPA-PET and BNCT in the context of malignant brain tumors, and assess the survival outcomes following BNCT. Methods: A cohort study was performed on patients who underwent BPA-PET between February 2017 and April 2022 in our hospital. Patients were stratified into two groups: those subjected to BNCT (Group 1) and those not (Group 2). The tumor to normal tissue (T/N) ratio derived from BPA-PET was set at 2.5. The findings were scrutinized based on clinical follow-up. Student's t-test and Chi-squared test were employed to discern differences between the groups. A cumulative survival curve was constructed employing the Kaplan-Meier method. Differences were considered statistically significant at P<0.05. Results: In total, 116 patients with T/N ratios obtained from BPA-PET were enrolled. BNCT was administered to 58 patients, while mortality was observed in 100 patients. The median overall survival (OS) for the two groups was 8.5 and 6.0 months, respectively. The cumulative OS exhibited no significant discrepancy between the two groups, nor in their T/N ratios. Within Group 1, 44 out of 58 (75.9%) patients exhibited T/N ratios exceeding 2.5. Excluding 3 patients who expired within 3 months, 55 out of 58 patients were evaluated for response after BNCT. The objective response rate (ORR) was 30.9%. Patients achieving ORR displayed substantially higher survival rates compared to those without (median OS 13.5 vs. 8.3 months, P=0.0021), particularly when T/N ratio exceeded 2.5 (median OS 14.8 vs. 9.0 months, P=0.0199). Conclusions: BNCT does not appear indispensable for prolonging the survival of patients afflicted with malignant brain tumors. Nevertheless, it proves advantageous when ORR is attained, a condition closely linked to the values of T/N ratio derived from BPA-PET.

Regorafenib combined with a PD-1 inhibitor in the second-line setting for unresectable hepatocellular carcinoma in real-world practice.

Background: Most advanced hepatocellular carcinoma (HCC) cases administered molecular targeted agents and/or anti-programmed cell death-1 (PD-1) inhibitors have no response or develop resistance. Moreover, second-line therapies still cannot provide beneficial clinical outcomes. A pilot study assessing combined regorafenib and PD-1 inhibitor as second-line treatment of advanced HCC reported promising effectiveness. Methods: The current single-center, retrospective, real-world study was carried out between January 2019 and July 2021. Advanced HCC cases were administered second-line regorafenib combined with a PD-1 inhibitor or regorafenib alone were assessed. Progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were determined. Results: Totally 46 HCC cases were analyzed, most of whom underwent previous systemic treatment comprising targeted therapy and immunotherapy. Tumor response was evaluated in 25 and 21 individuals in the regorafenib + PD-1 inhibitor and regorafenib monotherapy groups, respectively: ORRs were 21.7% and 8.7%, and DCRs were 47.8% and 32.6%, respectively. Median PFS was markedly longer in the regorafenib plus PD-1 inhibitor group (11.5 months) compared with the regorafenib monotherapy group (5.1 months, P=0.049). Conclusions: This study suggested regorafenib and a PD-1 inhibitor in combination may provide significant clinical benefits in HCC cases showing progression following first-line treatment. Further analysis in real-world studies with large cohorts is warranted to confirm these findings.

Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts.

BACKGROUND: The RET gene, which is frequently mutated across many types of cancer, has been proven to be critically involved in tumorigenesis and tumour development; however, its prediction of the therapeutic efficacy of immune checkpoint inhibitor (ICI) therapy remains to be elucidated. The present research aims to investigate the association between RET mutations and the efficiency of ICI therapy. METHOD: We analysed the role of RET mutations in predicting the prognosis of patients receiving ICIs therapy in the discovery cohort and validated it in the validation cohort. Then, multi-omics data from TCGA pan-cancer cohort was employed to propose the association between RET mutations and tumour inflamed anti-tumour immune response and tumour antigenicity. RESULTS: Our study revealed that among 606 cases and across five types of cancer, RET mutation was associated with better clinical outcomes for ICIs therapy, including elevated response rate, longer progression-free survival PFS, and longer overall survival OS. Multivariate analysis showed that RET mutation could independently predict the prognosis of patients treated with ICIs, after adjusting cancer types. The predictive value of RET status for the OS of patients treated with ICIs immunotherapy was further validated in the validation cohort (n = 1,409). Subgroup analysis suggested that only the monotherapy group showed significant differences in OS(P < 0.05) and PFS(P < 0.05) between RET-wildtype tumours and RET-mutant tumours. Multi-omics data analysis revealed potential anti-tumour immunity mechanisms of RET mutations, suggesting that RET-mutant tumours have enhanced immunogenicity, higher expression of immune checkpoints and chemokines, and higher immune cell infiltration than those observed in RET-wildtype tumours; thus, potentially indicating a more favourable response to immunotherapy. CONCLUSIONS: RET mutation may be a predictive biomarker of enhanced response to ICIs therapy. Extensive investigation of the underlying molecular mechanisms and prospective studies are needed in the future.

Treatment-free survival after discontinuation of immune checkpoint inhibitors in mNSCLC: a systematic review and meta-analysis.

Background: Recent research has suggested that patients with metastatic non-small cell lung cancer (mNSCLC) can achieve ongoing response after discontinuation of immune checkpoint inhibitor (ICI), but the best time to discontinue and the factors influencing efficacy remain unknown. Method: A systematic search was performed for prospective clinical trials in patients with mNSCLC treated with ICIs published up to July 10, 2022. Eligible studies reported treatment-free survival (TFS) after discontinuation of ICI in partial objective responders. We calculated objective response rate (ORR) and TFS using random-effects models with respective 95% confidence intervals (Cis), and performed subgroup analyses to discuss the specific associations between ORR and TFS and the associated influencing factors. Results: Across the 26 cohorts (3833 patients) included, the weighted mean ORR for all patients was 29.30% (95% CI 24.28% to 34.57%), with ICI plus chemotherapy (48.83%, 95% CI 44.36% to 53.30%) significantly higher than monotherapy (23.40%, 95% CI 18.53% to 28.62%). 395 patients were all patients who were complete or partial responders in the study, 194 discontinued ICI treatment, and nearly 35.5% achieved a durable response. No significant differences in TFS were found between subgroups according to the ICI regimen classification. Four cohorts of patients who completed 35 courses of treatment showed high levels of pooled TFS at 6 (80.18%, 95% CI 53.03% to 97.87%) and 12 months (66.98%, 95% CI 46.90% to 84.47%). Three cohorts of patients discontinued ICI treatment due to treatment-related adverse events (TRAEs) with the TFS rates at 6 (76.98%, 95% CI 65.79% to 86.65%) and 12 months (64.79%, 95% CI 50.20% to 78.19%). Conclusion: Patients with mNSCLC were able to achieve ongoing responses after discontinuation of ICI. In conclusion, the results of this meta-analysis indicate that different treatment regimens, different drugs or different treatment durations may have an impact on TFS.

Safety and Efficacy of Chimeric Antigen Receptor T-Cell Therapy for Glioblastoma: A Systemic Review and Meta-Analysis.

Background: Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment option for patients with refractory hematological malignancies. However, its efficacy in glioblastoma remains unclear. Here, we performed a systematic review to summarize the safety and efficacy of CAR T-cell therapy in glioblastoma. Methods: The PubMed, EMBASE, and Cochrane databases were searched to identify articles published before June 30, 2021 describing the use of CAR T-cell therapy in glioblastoma. Information on the toxicity of CAR T-cell therapy was summarized. The pooled objective response rate (ORR) and overall survival (OS) of patients who underwent CAR T-cell therapy were estimated using a random-effects model with an inverse-variance weighting model and quantile estimation method, respectively. Results: Of 397 articles identified, eight studies including 63 patients with recurrent glioblastoma treated with various CAR T-cell regimens were included in the analysis. Six (9.5%) patients developed cytokine release syndrome (grade ≤2), and 16 (25.4%) experienced non-critical neurological events. The pooled ORR was 5.1% (95% confidence interval [CI], 0.0-10.4; I 2 = 0.05%), and the pooled median OS was 8.1 months (95% CI, 6.7-9.5; I 2 = 0.00%). Conclusion: Although CAR T-cell therapy is a relatively safe therapeutic option in patients with glioblastoma, it shows marginal efficacy, suggesting that further research is necessary for its translation into clinical practice for the treatment of recurrent glioblastoma.

Real-World Data of Different Immune Checkpoint Inhibitors for Non-Small Cell Lung Cancer in China.

Background: Patients treated with immunotherapy in the real-world may have significantly different responses to those meeting inclusion criteria for random controlled clinical studies. There is a partial overlap in approved indications for the use of the different immune checkpoint inhibitors (ICIs) currently available. A comprehensive assessment of the efficacy, safety and economic effects of various ICIs is a problem that clinicians need to address. Methods: Analyzed real-world data was collected from non-small cell lung cancer (NSCLC) patients who were treated with ICIs from hospitalized patients in the Lung Cancer Center of Peking Union Medical College Hospital between 2018 and 2021. The objectives were to evaluate the efficacy and safety of different ICIs for the treatment of NSCLC in China and to investigate the factors affecting their curative effects. Results: Overall, 351 patients were included in the retrospective study. The median PFS for the NSCLC patient cohort treated with medication regimens that included ICIs was 9.5 months, with an ORR of 47.3%. There were no significant discrepancies in efficacy and safety between the different ICIs administered. Factors that had the greatest impact on the efficacy of ICIs were the disease stage, ECOG-PS scores and treatment lines. Gender, age, smoking history, PD-L1 TPS expression, history of targeted therapy and irAEs all had a degree of influence on patient prognosis. Conclusions: The study reports the experience of real-world usage of ICIs for the treatment of NSCLC patients in China. The results were generally consistent with those of clinical trials, while the efficacy and safety of different ICIs exhibited no statistically significant differences. Therefore, physicians can make a comprehensive choice based on the indications and cost of different ICIs and the preferences of patients.

Safety and efficacy of sintilimab combination therapy for the treatment of 48 patients with advanced malignant tumors.

Background: Sintilimab is a recombinant fully human anti-programmed death 1 (PD-1) monoclonal antibody that blocks the interaction of PD-1 with its ligand. We evaluated the safety and efficacy of sintilimab combined with chemotherapy and targeted therapy in the treatment of advanced malignant tumors. Methods: We performed a retrospective analysis of the clinical data of patients with advanced malignant tumors treated with sintilimab combined with chemotherapy and targeted therapy admitted to the Third Ward of the Department of Medical Oncology, First Affiliated Hospital of Anhui Medical University, China, from July 2019 to February 2021. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and related adverse reactions were analyzed. Results: A total of 48 patients with advanced malignant tumors treated with sintilimab combined with chemotherapy and targeted therapy. All 48 patients completed 2 courses of treatment, and the ORR and DCR were 20.83% and 81.25%. The median PFS for all patients in this study was 7 months, and the median OS was not yet reached. The median PFS for the first-line and second-line patients was 10 months, and the median OS was not yet reached. The median PFS for third-line and beyond patients was 7 months, and the median OS was 10 months. The differences in PFS and OS were both statistically significant. Adverse events occurred in 24 patients, of which 18 patients had grade I-II adverse events and 6 patients had grade III-IV adverse events. Conclusions: Sintilimab is an inexpensive PD-1 drug produced in China. Sintilimab combination therapy showed good safety in the treatment of advanced malignant tumors, with increases in the treatment efficacy and DCR for advanced tumors. Because of few adverse reactions and proven efficacy, sintilimab combination therapy can be used as an option for the treatment of advanced malignant tumors.

Overall Treatment Strategy for Patients With Metastatic NSCLC With Activating EGFR Mutations.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are standard of care in the first-line (1L) setting for patients with metastatic non-small cell lung cancer (mNSCLC) with activating EGFR mutations. EGFR-activating mutations are a predictive factor for response to EGFR-TKIs. Meta-analyses have shown that patients with exon 21_L858R mutations exhibit reduced sensitivity to EGFR-TKIs, resulting in inferior patient outcomes compared to those with exon 19 deletion mutations, with worse overall survival, progression-free survival, objective response, and disease control rates. Clinical activity observed with 1L therapy with first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKIs is not permanent, and resistance inevitably develops in all cases, supporting the importance of overall treatment planning. The introduction of the 3G EGFR-TKI, osimertinib, provides an opportunity to overcome T790M-mediated resistance to 1G, and 2G EGFR-TKIs. Additionally, with the use of osimertinib, fewer T790M mutations are being detected as T790M is not a reported resistance mechanism to 3G EGFR-TKIs. However, there are currently no approved targeted therapies after 3G EGFR-TKIs. In order to further improve patient outcomes, there is a need to explore additional options for the overall treatment strategy for patients, including 1L and beyond. Combination of vascular endothelial growth factor (VEGF) inhibitors and EGFR-TKIs or chemotherapy and EGFR-TKIs may be a potential therapeutic approach in the 1L setting. This review discusses current treatment options for mNSCLC with activating EGFR mutations based on tumor, patient, and treatment characteristics and how an overall treatment plan may be developed.

Comprehensive study of neoadjuvant targeted therapy for resectable non-small cell lung cancer.

BACKGROUND: Approximately 30-70% percent of patients with non-small cell lung cancer (NSCLC) still relapse after receiving complete resection and even suffer distant metastasis. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have gradually replaced chemotherapy to become the first-line postoperative NSCLC treatment because they can effectively inhibit the postoperative recurrence of lung cancer. However, the clinical efficacy of neoadjuvant EGFR-TKIs in EGFR mutant NSCLC patients is still unclear. The purpose of this study was to evaluate their clinical efficacy and to further explore factors affecting recurrence in such patients. METHODS: EGFR-mutated patients receiving neoadjuvant EGFR-TKI treatment in our hospital from July 2016 to September 2020 were retrospectively included. These patients underwent radical tumor resection after treatment. The primary endpoint was the objective response rate (ORR). The secondary endpoints were the major pathological response (MPR), disease-free survival (DFS), and overall survival (OS). RESULTS: A total of 42 patients who met the inclusion criteria were included in this study. The ORR was 47.6% (20/42), and the MPR was 23.8% (10/42). The average follow-up time was 23.7 months. As of the final follow-up date, 18 (42.9%, 18/42) patients had experienced tumor recurrence. Of these, there were 11 (61.1%) cases of local recurrence and 7 (38.9%) cases of distant metastasis, including 5 bone metastases and 2 brain metastases. Multivariate Cox regression results showed that the high-risk subtype [P=0.012, hazard ratio (HR) =24.560; 95% confidence interval (CI), 2.016-299.227] was a risk factor for postoperative recurrence. Patients with a high-risk subtype (solid or micropapillary subtype) had significantly worse recurrence-free survival (RFS, log-rank P=0.032). Although patients with pathological remission had a similar RFS as patients who did not achieve pathological remission (log-rank P=0.069), the patients without pathological remission showed a tendency toward a worse prognosis. CONCLUSIONS: Neoadjuvant EGFR-TKIs had good effects on EGFR-mutant NSCLC patients at different stages, especially those with MPR. Patients with high-risk subtypes (solid or micropapillary) should be closely followed up after surgery because of the high risk of recurrence.

Target therapy for metastatic alveolar soft part sarcoma: a retrospective study with 47 cases.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a translocation-associated soft-tissue tumor resistant to conventional cytotoxic agents. This report aims to compare the efficacy of anlotinib versus pazopanib as targeted monotherapy in metastatic ASPS and to determine the impact of drug dosage reduction on disease control. METHODS: Sixteen and 31 patients with metastatic ASPS were respectively treated with anlotinib and pazopanib monotherapy at a single institution. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were retrieved and compared between both therapeutic arms. Adverse events (AEs) within each group were recorded. Kaplan-Meier survivorship curves computed the impact of drug dosage reduction on PFS. RESULTS: The anlotinib group showed an ORR of 31.2%, compared to 35.5% in the pazopanib arm (P=0.772). Median PFS was 23.6 months [95% confidence interval (CI), 16.2-31.0 months] in patients treated with anlotinib, but dropped to 13.7 months (95% CI, 10.8-16.7 months) in those managed with pazopanib (P=0.023). One (6.3%) patient on anlotinib and 11 (35.5%) on pazopanib developed AEs requiring drug dosage reduction (P=0.029), which significantly reduced patients' PFS in the latter setting (10.5 vs. 15.8 months, P=0.012). In patients without dosage reduction, anlotinib showed a bordering advantage than pazopanib on median PFS (24.5 vs. 15.8 months, P=0.112). CONCLUSIONS: Compared to pazopanib, anlotinib yielded longer PFS and lower incidence of AEs in ASPS patients. Drug dosage reduction was more frequently encountered with the former agent and affected the disease control.

Analysis of the relationship between Ki-67 expression and chemotherapy and prognosis in advanced non-small cell lung cancer.

BACKGROUND: To analyse the relationship between the Ki-67 index of advanced non-small cell lung cancer (NSCLC) and the objective response rate (ORR) and progression-free survival (PFS) of patients who received chemotherapy. METHODS: The Ki-67 index of advanced NSCLC pathology was established by immunohistochemistry; using univariate and multivariate analyses, we retrospectively analysed the relationship between the Ki-67 index of 112 advanced NSCLC patients in our hospital and chemotherapy response and PFS. Both epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) were found to be wild type in adenocarcinoma patients, and no gene testing was performed for those with squamous cell carcinoma. All selected patients received four cycles of platinum-based chemotherapy, and according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), the curative effect was evaluated after every two cycles. RESULTS: In the univariate and multivariate analyses, the Ki-67 index was significantly associated with the objective response to chemotherapy (B =-0.069, P=0.000). Ki-67 expression could also accurately predict the ORR of chemotherapy [P<0.0001, area under the curve (AUC) =0.7467, 95% confidence interval (CI): 0.6578-0.8356]: squamous cell carcinoma group [P=0.0003, AUC =0.8065 (95% CI: 0.6922-0.9208)], adenocarcinoma group [P=0.0193, AUC =0.6810 (95% CI: 0.5360-0.8262)]. The overexpression of Ki-67 was a negative prognostic factor for PFS in advanced NSCLC (P<0.0001): squamous cell carcinoma (P=0.0055), adenocarcinoma (P<0.0001). According to the multivariate Cox analysis, Ki-67 index (P=0.000) and stage (P=0.001) were negative factors of PFS. CONCLUSIONS: The Ki-67 index might be a clinically significant biomarker in advanced NSCLC and may be able to predict the efficacy of chemotherapy. High expression of Ki-67 might also be an indicator of shortened PFS time.

The efficacy and safety of PD-1/PD-L1 inhibitors in breast cancer: a systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibition has been increasingly used in breast cancer therapy. Understanding the benefit and risk of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors is critical for clinical practice. This study aims to determine the objective response, disease control and adverse events of breast cancer patients treated with PD-1/PD-L1 inhibitors. METHODS: PubMed, Cochrane Library, Web of Science and EMBASE databases were searched up to Aug 1, 2019. Both nonrandomized and randomized studies were included. Pooled objective response rate (ORR), disease control rate (DCR) and adverse events were pooled analyzed. RESULTS: A total of nine clinical studies were identified. Triple-negative breast cancer (TNBC) showed the highest estimates of ORR [overall population: 49.7%, 95% confidence interval (CI): 33.9-65.5%; PD-L1 positive population: 55.8%, 95% CI: 42.9-68.8%] and DCR (overall population: 67.5%, 95% CI: 38.6-96.4%; PD-L1 positive population: 83.4%, 95% CI: 72.2-94.5%) post-anti-PD-L1 plus nab-paclitaxel treatment. With respect to grade ≥3 treatment related adverse events, the pooled estimates ranged from 12.0% to 50.9% for anti-PD-1/PD-L1 monotherapy. The pooled estimates percentages of grade ≥3 treatment related adverse events in TNBC patients treated with anti-PD-L1 plus nab-paclitaxel were 59.6% (95% CI: 36.1-83.0). CONCLUSIONS: We presented the aggregate estimates of ORR, DCR, and treatment related adverse events for breast cancer patients receiving anti-PD-1/PD-L1 treatment. However, these results were largely derived from single-arm studies, and randomized studies with head-to-head comparison of PD-1/PD-L1 inhibitors and chemotherapy are lacking. Additionally, the incidence of varying treatment related adverse events should be also carefully monitored.