Pooled Objective Response Rate Research Articles

Efficacy of immunotherapy in patients with oncogene-driven non-small-cell lung cancer: a systematic review and meta-analysis.

Immunotherapy is an emerging antitumor therapy that can improve the survival of patients with advanced non-small-cell lung cancer (NSCLC). However, only about 20% of NSCLC patients can benefit from this treatment. At present, whether patients with driving gene-positive NSCLC can benefit from immunotherapy is one of the hot issues. Therefore, we conducted a meta-analysis to evaluate the efficacy of immunotherapy in patients with oncogene-driven NSCLC and concluded the efficacy of altered subtypes. A literature search was performed using PubMed, Web of Science, and Cochrane databases. The primary endpoints included the objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients with oncogene-driven NSCLC. In all, 86 studies involving 4524 patients with oncogene-driven NSCLC were included in this meta-analysis. The pooled ORRs in clinical trials treated with monoimmunotherapy of EGFR, ALK, and KRAS alteration were 6%, 0%, and 23%, respectively. In retrospective studies, the pooled ORRs of EGFR, ALK, KRAS, BRAF, MET, HER2, RET, and ROS1 alteration were 8%, 3%, 28%, 24%, 23%, 14%, 7%, and 8%, respectively. Among them, the pooled ORRs of KRAS non-G12C mutation, KRAS G12C mutation, BRAF V600E mutation, BRAF non-V600E mutation, MET-exon 14 skipping, and MET-amplification were 33% 40%, 20%, 34%, 17%, and 60%, respectively. In addition, the pooled mPFS rates of EGFR, KRAS, MET, HER2, and RET alteration were 2.77, 3.24, 2.48, 2.31, and 2.68 months, while the pooled mOS rates of EGFR and KRAS alteration were 9.98 and 12.29 months, respectively. In prospective data concerning EGFR mutation, the pooled ORR and mPFS treated with chemo-immunotherapy (IC) reached 38% and 6.20 months, while 58% and 8.48 months with chemo-immunotherapy plus anti-angiogenesis therapy (ICA). Moreover, the pooled mPFS and mOS of monoimmunotherapy was 2.33 months and 12.43 months. EGFR-, ALK-, HER2-, RET-, and ROS1-altered NSCLC patients have poor reactivity to monoimmunotherapy but the efficacy of immune-based combined therapy is significantly improved. KRAS G12C mutation, BRAF non-V600E mutation, and MET amplification have better responses to immunotherapy, and more prospective studies are needed for further research.

Efficacy and safety of camrelizumab combined with TACE for hepatocellular carcinoma: a systematic review and meta-analysis.

Hepatocellular carcinoma (HCC) represents a highly lethal and recurrent neoplasm, with limited effective treatment regimens available. Camrelizumab, as a novel PD1 inhibitor combined with transcatheter arterial chemoembolization (TACE), has been widely used in the treatment of HCC. However, there remains a contentious debate regarding the clinical value of the TACE and camrelizumab combination. This study seeks to investigate the efficacy and safety of this combination treatment regimen in patients with HCC. The related studies were retrieved from four online databases, including Pubmed, Cochrane Library, EMBASE, and Web of Science, up to June 1, 2023. The selection of studies was based on screening of titles, abstracts, and full-texts. The primary efficacy outcomes included complete response (CR), objective response rate (ORR), and disease control rate (DCR), while safety outcomes evaluated all treatment-related adverse events (AEs). Additionally, secondary outcomes such as overall (OS) and progression-free survival (PFS) were extracted for further survival analysis. The quality of the included trials was assessed using the MINORS tool. Publication bias was evaluated through funnel plot and Egger's test. A total of 17 publications involving 1,377 cases were included. The pooled CR rate, ORR, and DCR of the patients treated with TACE plus camrelizumab had a pooled CR rate of 8% (95% CI: 0.01-0.15, p=0.03), ORR of 47% (95% CI: 0.42-0.52, p<0.00001) and DCR of 82% (95% CI: 0.77-0.88, p<0.00001), respectively. Compared with a control group that did not receive TACE or camrelizumab, the pooled RR of CR rate, ORR, and DCR were 1.61 (95% CI: 1.27-2.04, p<0.0001), 1.56 (95% CI: 1.19-2.05, p=0.001) and 1.55 (95% CI: 1.19-2.03, p=0.001), respectively. Besides, the combination regimen can prolong the OS (HR=2.60, 95% CI: 2.25-3.02, p<0.00001) and PFS (HR=4.90, 95% CI: 1.94-12.38, p=0.0008). However, the incidence of treatment-related AEs was relatively high (77%), with 29% for grade 3 AEs. The most common AEs observed were pain (47%), fever (46%), hepatic function abnormalities (44%), hypoalbuminemia (39%), and hypertension (37%). The combination treatment did not increase the incidence of AEs compared to the control group, except for the hand-foot skin reaction (RR=0.85, 0.74-0.97, p=0.01), hepatic encephalopathy (RR=4.29, 2.51-7.35, p<0.00001) and nausea (RR=1.35, 1.13-1.61, p=0.001). Combination therapy of TACE plus camrelizumab has shown notable clinical benefits, improved survival, and a manageable safety profile in patients with HCC, but it is essential to monitor and manage the specific toxicities, especially for the camrelizumab-related AEs.

A review and metanalysis of metronomic oral single-agent cyclophosphamide for treating advanced ovarian carcinoma in the era of precision medicine.

Oral metronomic cyclophosphamide has been used as a single agent or in combination with other drugs for several solid tumors with interesting results in disease palliation and mild to moderate toxicity, notably in patients with recurrent epithelial ovarian cancer (EOC) progressing after systemic chemotherapy. In this paper, we report a review and a metanalysis of heterogeneous data published up to date. The literature search was restricted to single-agent MOC. The analysis was conducted through March 2023 by consulting PubMed, Embase, Google Scholar, and The Cochrane Library databases. Research string and Medical Subject Headings included "ovarian tumor," "ovarian carcinoma," or "ovarian cancer," "fallopian tube cancer," "primary peritoneal cancer," "oral chemotherapy," and "metronomic cyclophosphamide." All articles were assessed for quality by at least two investigators independently, and a < 18 patients sample size cutoff was chosen as a lower limit with a Cohen's kappa statistical coefficient for accuracy and reliability. Metanalysis of selected papers was carried out according to a fixed model. The percentage of agreement between investigators on literature study selection was very high, reaching 96.9% with a Cohen's k of 0.929. MOC pooled objective response rate (ORR) and disease control rate for recurrent or platinum-refractory ovarian cancer were 18.8% (range 4-44%) and 36.2% (range 16-58.8%), respectively. The mean progressive-free survival and overall survival were 3.16 months (range 1.9 to 5.0 months) and 8.7 months (range 8 to 13 months), respectively. The fixed model metanalysis of selected studies showed a 16% median ORR (12-20% CI, p < 0.001). Single-agent oral cyclophosphamide in EOC holds promise as a treatment option, even in the era of precision medicine. Genetic factors, such as DNA repair gene polymorphisms, may influence treatment response. Combining cyclophosphamide with biological agents such as PARP inhibitors or immunotherapy agents is an area of active investigation.

Triple combination of HAIC-FO plus tyrosine kinase inhibitors and immune checkpoint inhibitors for advanced hepatocellular carcinoma: A systematic review and meta-analysis.

The triple combination of hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitors (ICIs) is expected to have a synergistic anticancer effect in HCC. We conducted this meta-analysis to evaluate the efficacy and safety of the triple combination treatment in advanced HCC patients. PubMed, Embase, Cochrane Library, Web of Science databases were systematically searched for relevant studies from the inception of each database to May 10, 2023. All articles focusing the triple combination treatment of HAIC-FO plus TKI and ICIs for advanced HCC were eligible. The meta-analysis was conducted following the PRISMA guidelines. The risk of bias was assessed using the Joanna Briggs Institute (JBI) for case series and Newcastle-Ottawa Scale (NOS) for cohort studies. The primary outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR). The secondary results were adverse events. Further meta-analysis of control studies demonstrated the superiority of the triple combination modality to TKI plus ICIs, and TKI alone. Nine articles (four cohort studies and five one-arm studies) involving 777 advanced HCC patients were included in this meta-analysis. In terms of survival analysis, the pooled median PFS was 11 months (95% CI: 10.1-12.0 months) with low heterogeneity (I2 = 0%, p = 0.97). With regard to tumor response, the pooled ORR and DCR was 61.6% (I2=0%, p = 0.71) and 87.9% (I2 = 13%, p = 0.33) with low heterogeneity, respectively. As compared with TKIs plus ICIs, and TKIs alone, the triple combination thrapy was associated with improved median OS (HR=0.51, 95%CI 0.41-0.62) with low heterogeneity across studies (I2 = 0%, p = 0.47), median PFS (HR=0.51, 95%CI 0.41-0.64) with low heterogeneity across studies (I2 = 0%, p = 0.41), ORR (RR = 0.56, 95% CI: 0.42-0.74) with high heterogeneity across studies (I2 = 69%, p = 0.02), and DCR (RR = 0.38, 95%CI 0.27-0.54) with low heterogeneity across studies (I2 = 14%, p = 0.32). The most common 3/4 AEs were elevated ALT and AST, thrombocytopenia, hypertension, nausea and vomiting in this meta-analysis. The triple combination therapy of HAIC-FO plus TKI and ICIs showed promising efficacy and safety in patients with advanced HCC. The protocol was registered with PROSPERO (ID:CRD42023424281).

A Meta-Analysis to Assess the Efficacy of HER2-Targeted Treatment Regimens in HER2-Positive Metastatic Colorectal Cancer (mCRC).

Recent trials provide evidence that HER2 is a potential new target for patients with colorectal cancer. While HER2-positive tumors do not show a very encouraging response to anti-HER2-positive agents like trastuzumab alone, promising results have been observed when combined with other synergistically acting tyrosine kinase inhibitors (TKIs). Our meta-analysis was conducted following the Cochrane Handbook and written following the PRISMA guidelines. The protocol was registered on PROSPERO with the registration number CRD42022338935. After a comprehensive search for relevant articles, 14 CTs were identified and uploaded to Rayyan, and six trials were ultimately selected for inclusion. The meta-analysis revealed that a median of three prior lines of therapy was used before enrolling in the six trials comprising 238 patients with HER2-positive metastatic colorectal cancer (mCRC). The pooled objective response rate (ORR) and disease control rate (DCR) were 31.33% (95% confidence interval [CI] 24.27-38.39) and 74.37% (95% CI 64.57-84.17), respectively. The pooled weighted progression-free survival (PFS) was 6.2 months. The pooled ORR and DCR meta-analysis indicate a significant response to HER2-targeted therapy in this patient in HER2-positive mCRC. Additionally, a pooled PFS of 6.2 months suggests that HER2-targeted treatment regimens are associated with a meaningful improvement in survival outcomes in this population.

Efficacy and safety of immune checkpoint inhibitor rechallenge in non-small cell lung cancer: A systematic review and meta-analysis.

The aim of the study was to explore the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with non-small cell lung cancer (NSCLC). Studies that enrolled NSCLC patients treated with two lines of ICIs were included using four databases. The initial line (1L-) and subsequent lines (2L-) of ICIs were defined as 1L-ICI and 2L-ICI, respectively. A total of 17 studies involving 2100 patients were included. The pooled objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and median overall survival (mOS) for 2L-ICIs were 10%, 50%, 3.0 months, and 13.1 months, respectively. The 2L-ICI discontinuation rates caused by toxicities ranged from 0% to 23.5%. Original data were extracted from six studies, covering 89 patients. Patients in whom 1L-ICIs were discontinued following clinical decision (the mPFS of 2L-ICIs was not reach) achieved a more prolonged mPFS of 2L-ICIs than those due to toxicity (5.2 months) and progressive disease (2.1 months) (p < 0.0001). Patients' 1L-PFS for more than 2-years had preferable 2L-ORR (35.0% vs. 9.8%, p = 0.03), 2L-DCR (85.0% vs. 49.0%, p = 0.007), and 2L-mPFS (12.4 vs. 3.0 months, p < 0.0001) than those less than 1-year. Patients administered the same drugs achieved a significantly prolonged mPFS compared with the remaining patients (5.4 vs. 2.3 months, p = 0.0004), and those who did not accept antitumor treatments during the intervals of two lines of ICIs achieved a prolonged mPFS compared to those patients who did accept treatments (7.6 vs. 1.9 months, p < 0.0001). ICI rechallenge is a useful therapeutic strategy for NSCLC patients, especially suitable for those who achieve long-term tumor remission for more than 2-years under 1L-ICIs.

Efficacy and safety of pembrolizumab in advanced neuroendocrine tumors (NETs): A meta-analysis of clinical trials.

165 Background: Patients with recurrent or metastatic neuroendocrine tumors (NETs) have limited treatment options and a poor prognoses. Programmed death–ligand 1 (PD-L1) has been associated with the pathogenesis, progression, and prognosis of NETs. This article analyzes the efficacy and safety profile of PDL1 inhibitor Pembrolizumab in advanced NETs. Our objective is to identify all the clinical trials in which Pembrolizumab has been assessed in treating NETs and to evaluate the efficacy and safety profile in this patient population with high power. Methods: Systemic searches of PubMed, the Cochrane Library, and ClinicalTrials.gov were conducted with prespecified terms. The outcomes studied in our analysis were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and serious adverse events (AEs). We calculated the pooled ORR for these studies using weighted pooled ORR = Σ (ORR_i * weight_i). We calculated the standard error using the formula SE = √(Σ (wi x (1 - ORRi) x ORRi) / Σ (wi x ni)) and the 95% confidence interval using the formula CI = ORR ± (1.96 x SE). This statistical method was also used to calculate our study's pooled DCR, PFS, OS, and serious AEs. However, it is essential to note that the pooled data is only as reliable as the individual data estimates from each study and may be subject to bias or confounding factors. Results: Five clinical trials met the inclusion criteria, including patients with gastrointestinal, pancreatic, lung, and lower genital tract NETs. Outcome data were available for all five studies, comprising 177 patients with NETs who received Pembrolizumab as part of the treatment regimen (Table). The pooled ORR and DCR were 5.27% (95% CI 2.23-8.31) and 5.4% (95% CI 3-7.8), respectively. The pooled weighted PFS was 4.4 months, and pooled weighted OS was 23.3 months. These findings suggest that Pembrolizumab has a promising ORR, DCR, PFS, and OS. Safety was a secondary endpoint, and the pooled serious AEs were noted in 20.9% of patients. Conclusions: Pembrolizumab demonstrated statistically significant efficacy and safety profile in a subset of patients with NETs and was overall well-tolerated. In recent years, the combination strategy of tyrosine kinase inhibitors (TKI) with PDL-1 checkpoint inhibitors has shown promising clinical benefits in patients with various solid tumors. Further studies are needed to analyze the efficacy and safety of TKI with PD-L1 inhibitors in NETs. [Table: see text]

Neoadjuvant immunotherapy for resectable hepatocellular carcinoma: a systematic review and meta-analysis.

Immune checkpoint inhibitors have initiated a new era in hepatocellular carcinoma (HCC) treatment. For improving the prognosis of patients with resectable HCC and reducing postoperative recurrence, immunotherapy is being developed in the neoadjuvant setting. However, the efficacy and safety of neoadjuvant immunotherapy remain unclear. PubMed, Embase, Medline, and Cochrane Library databases were systematically searched for the clinical trials of neoadjuvant immunotherapy for resectable HCC. A single-arm meta-analysis was conducted to calculate the odds ratio and 95% confidence interval (CI), and statistical transformation was performed to obtain the pooled rate P(t) and its CI. Subgroup analyses were performed according to the type of combination therapy. 81 patients from four studies were included in this meta-analysis. In patients with resectable HCC, the pooled major pathological response (MPR) rate and pathological complete response (pCR) rate for neoadjuvant immunotherapy were 0.23 (95% CI, 0.14-0.36) and 0.19 (95% CI, 0.10-0.30), respectively. The pooled objective response rate (ORR) was 0.18 (95% CI, 0.10-0.28), comparable to the results of immunotherapy for advanced HCC. The overall treatment-related adverse events (TRAE) rate was 0.80 (95% CI, 0.68-0.89), but the grade ≥3 TRAE rate was low at 0.21 (95% CI, 0.13-0.33). The pooled surgical resection rate and surgical delay rate were 0.95 (95% CI, 0.85-0.98) and 0.05 (95% CI, 0.02-0.16), respectively. Subgroup analyses revealed no significant differences in clinical outcomes between immunotherapy combinations. This meta-analysis provides preliminary evidence of the efficacy and safety of neoadjuvant immunotherapy for HCC, suggesting that it is a promising perioperative treatment option. Conclusive evidence supporting its use requires additional data from large-scale clinical trials.

Efficacy of fibroblast growth factor receptor (FGFR) inhibitors therapy in advanced cholangiocarcinoma with FGFR genes alterations: A meta-analysis of phase II clinical trials.

54 Background: Fibroblast growth factor receptor ( FGFR) gene fusions and rearrangements are involved in the pathogenesis of approximately 10 to 16 percent of patients with cholangiocarcinoma. There is no meta-analysis available of phase 2 clinical trials of FGFR inhibitors in these patients. In this article, we analyze the efficacy of FGFR inhibitors in advanced cholangiocarcinoma with FGFR gene fusions or other rearrangements. Methods: Systemic searches of PubMed, Embase, the Cochrane Library, Google Scholar, and ClinicalTrials.gov were conducted with prespecified terms. The outcomes studied in our analysis were Objective response rate (ORR), Disease control rate (DCR), Progression-free survival (PFS), and Overall survival (OS). We calculated the pooled ORR for these studies by using weighted average ORR = Σ (ORR_i * weight_i). Calculate the standard error using the formula SE = √(Σ (wi x (1 - ORRi) x ORRi) / Σ (wi x ni)) and the 95% confidence interval using the formula CI = ORR ± (1.96 x SE). However, it is important to note that the pooled ORR is only as reliable as the individual ORR estimates from each study and may be subject to bias or confounding factors. This method was used to calculate the pooled DCR, PFS, and OS for our study as well. All data extraction and calculations were verified by three reviewers. Results: Eight phase II clinical trials met the inclusion criteria (1-8). Outcome data were available for all eight studies, comprising 562 patients with FGFR-positive advanced cholangiocarcinoma who received FGFR-targeted treatment regimens. The pooled objective response rate (ORR) and disease control rate (DCR) were 32.6% (95% CI 28.1-37.1) and 81.86% (95% CI 74.96-88.76), respectively. The pooled weighted progression-free survival (PFS) was 7.5 months, and pooled overall survival (OS) was 17.4 months. These findings suggest that FGFR-targeted treatment regimens have a promising ORR, DCR, PFS, and OS. Conclusions: FGFR inhibitors as a class in patients with advanced or metastatic cholangiocarcinoma with FGFR gene alterations showed clinically meaningful efficacy with durable objective responses. [Table: see text]

Comparison of tumor-agnostic and tumor-specific clinical oncology trial designs: a systematic review and meta-analysis.

Aim: To examine whether tumor-specific and tumor-agnostic oncology trials produce comparable estimates of objective response rate (ORR) in BRAF-altered cancers. Materials & methods: Electronic database searches were performed to identify phase I-III clinical trials testing tyrosine kinase inhibitors from 2000 to 2021. A random-effects model was used to pool ORRs. A total of22 cohorts from five tumor-agnostic trialsand 41 cohorts from 27 tumor-specific trials had published ORRs. Results: There was no significant difference between pooled ORRs from either trial design for multitumor analyses (37 vs 50%; p=0.05); thyroid cancer (57 vs 33%; p=0.10); non-small-cell lung cancer (39 vs 53%; p=0.18); or melanoma (55 vs 51%; p=0.58). Conclusion: For BRAF-altered advanced cancers, tumor-agnostic trials do not yield substantially different results from tumor-specific trials.

UNMET NEED IN RELAPSED/REFRACTORY (R/R) MANTLE CELL LYMPHOMA (MCL) POST‐BRUTON TYROSINE KINASE INHIBITOR (BTKI): A SYSTEMATIC LITERATURE REVIEW AND META‐ANALYSIS

Background: Most patients with MCL, a rare B-cell non-Hodgkin lymphoma, will relapse or become refractory to treatment. While the introduction of BTKis has been transformative, options for patients who fail to respond or whose disease progresses on BTKis remain limited and largely palliative in nature. We sought to characterize and quantify the unmet clinical need of patients with R/R MCL in the post-BTKi setting. Methods: MEDLINE, Embase, and CENTRAL were systematically searched to October 2022—supplemented with hand searches of select conferences—to identify studies reporting overall survival (OS), progression-free survival (PFS), and/or response outcomes of patients receiving non-CAR-T treatments or brexucabtagene autoleucel (brexu-cel) in the post-BTKi setting. Random effects bivariate meta-analyses of OS/PFS were conducted based on studies with published Kaplan-Meier (KM) curves from which individual patient data could be estimated. Response outcomes, based on the best response achieved, were meta-analyzed using a generalized linear mixed model. Outcomes were evaluated separately for patients treated with non-CAR-T and brexu-cel. Results: Twenty-six studies (23 observational; 3 trials), reporting the outcomes of 1845 patients treated from 2005 to 2022, were included, where patients were initially enrolled for treatment with a BTKi (12 studies) or for treatment post-BTKi (14 studies). The non-CAR-T interventions varied, with most studies reporting outcomes from cohorts of patients receiving a variety of interventions. Across the included studies, most patients were male (65-94%) and older, with the median age varying from 63 to 77 years. OS and PFS KM curves were published in 10 and 3 studies, respectively, for non-CAR-T outcomes. The pooled median OS/PFS for these patients was 9.1 and 7.6 months, respectively (Table 1). The pooled objective response rate (ORR) and percentage of patients achieving a complete response (CR) were 45% and 23%, respectively. The median OS/PFS of patients who received brexu-cel was 32.1 and 14.9 months, based on 5 and 6 studies with KM curves, respectively, with ORR/CR rates of 89% and 74%. Analyses were not sensitive to different survival distributions or fixed/random effects models. Conclusions: Treatment options in the post-BTKi setting are heterogeneous and a significant unmet clinical need persists. Though longer follow-up is needed for survival outcomes, treatment with brexu-cel is emerging as a promising option in this difficult-to-treat setting. The research was funded by: This study was funded by Kite, a Gilead company. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies Conflicts of interests pertinent to the abstract M. Dreyling Consultant or advisory role Astra Zeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, Roche Research funding: Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche Educational grants: Janssen, Roche Other remuneration: Astra Zeneca, Gilead/Kite, Janssen, Lilly, Novartis, Roche B. Shah Consultant or advisory role Pepromene Bio; Takeda Honoraria: Kite/Gilead; BMS; Novartis; Amgen; Pfizer; Beigene; Adaptive; Century Therapeutics; Autolus Research funding: Kite; Servier; Jazz Pharma Educational grants: Kite/Gilead; Takeda Other remuneration: Chair, NCCN Adult ALL subcommittee J. Wu Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead; Amgen; Abbott; AbbVie; Avid; Curis; Viracta T. Itani Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead Sciences M. J. Zoratti Research funding: RainCity Analytics has received funds from for-profit healthcare companies for research S. Kanters Research funding: RainCity Analytics has received funds from for-profit healthcare companies for research S. W. Wade Consultant or advisory role Kite Pharma; Amgen; Allergan/Abbvie; Johnson & Johnson W. Peng Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead J. Castaigne Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead I. Kloos Employment or leadership position: Kite, a Gilead company Stock ownership: Gilead Sciences M. Wang Consultant or advisory role AbbVie; Acerta Pharma; ADC Therapeutics America; Amphista Therapeutics Limited; AstraZeneca; Be Biopharma; BeiGene; BioInvent; Deciphera; DTRM Biopharma (Cayman) Limited; Genentech; InnoCare; Janssen; Kite Pharma; Leukemia & Lymphoma Society; Lilly; Merck; Miltenyi Biomedicine; Milken Institute; Oncternal; Parexel; Pepromene Bio; Pharmacyclics; VelosBio Honoraria: AbbVie; Acerta Pharma; AstraZeneca; Bantam Pharmaceutical; BeiGene; BioInvent; Bristol Myers Squibb; CAHON; Dava Oncology; Eastern Virginia Medical School; Genmab; i3Health; IDEOlogy Health; Janssen; Kite Pharma; Leukemia & Lymphoma Society; Medscape; Meeting Minds Experts; MD Education ; MJH Life Sciences; Merck; Moffit Cancer Center; Nurix; Oncology Specialty Group; OncLive; Pharmacyclics; Physicians Education Resources (PER); Practice Point Communications (PPC); Studio ER Congressi Research funding: Acerta Pharma; AstraZeneca; BeiGene; BioInvent; Celgene; Genmab; Genentech; Innocare; Janssen; Juno Therapeutics; Kite Pharma; Lilly; Loxo Oncology; Molecular Templates; Oncternal; Pharmacyclics; VelosBio; Vincerx

Response to immune checkpoint inhibitor (ICI) rechallenge in patients with metastatic renal cell carcinoma who progressed on prior ICI: A systematic review and meta-analysis.

4547 Background: Several immune checkpoint inhibitor (ICI)-based combination regimens are standard-of-care for first-line treatment of metastatic renal cell carcinoma (mRCC). These include dual ICI and ICI-tyrosine kinase inhibitor (TKI) combinations. While single-agent ICI is recommended as subsequent-line therapy for ICI-naïve patients, there is limited knowledge regarding efficacy of rechallenging with a different ICI or using different ICI combinations in patients who have progressed on prior ICI therapy. This is a clinically critical question as most mRCC patients would have already received ICI therapy at progression. The aim of this study is to address the above by performing a systematic review and meta-analysis. Methods: PubMed, Cochrane Library and Web of Science were systematically searched to identify studies of later-line ICI rechallenge after progression on any previous ICI in mRCC patients from database inception to December 31st, 2022. Patients who had progressed on prior ICI and rechallenged with ICI as single agent/dual/TKI combination as any subsequent line of therapy in both retrospective and prospective studies were included. Exclusion criteria were phase I or any phase studies combining ICI with unapproved drugs, case reports and case series. We calculated the pooled objective response rate (ORR) and disease control rate (DCR) using mixed effects model treating individual studies as a random effect. We further stratified studies into prospective and retrospective and performed subgroup analyses. Results: A total of 11 studies, 6 prospective and 5 retrospective with a total of 603 patients were initially identified. Out of the 6 prospective studies, 3 had an adaptive design of using salvage ipilimumab/nivolumab in patients who had either progressed or had stable disease as the best overall response on nivolumab monotherapy. These studies were excluded as they did not meet our inclusion criteria. A total of 8 studies with 400 patients were included in the final analysis. The ORR was 28% (95% CI, 0.27-0.36) and the DCR was 70% (95% CI, 0.47-0.85) with no significant differences between prospective and retrospective studies. Our ORR is higher than an earlier meta-analysis reporting an ORR of 14% with salvage ipilimumab/nivolumab after previous treatment with ICI. Conclusions: This meta-analysis demonstrates a modest ORR and an impressive DCR. Therefore, it provides strong clinical rationale to consider rechallenging with ICI-based therapy for later-line treatment of mRCC patients who have progressed on prior ICI. [Table: see text]

Abstract P5-02-52: Predictive and prognosis value of PIK3CA mutations in HER2-positive breast cancer treated with tyrosine kinase inhibitors (TKIs): a systemic review and meta-analysis

Abstract Background: PIK3CA mutations is one of the most frequent gene alterations in breast cancers, which was reported to be related to the treatment response of anti-HER2 regimens. However, the relationship between PIK3CA mutations and treatment response of a tyrosine kinase inhibitors (TKIs) is still unclear. We thus conducted a systemic review and meta-analysis to investigate the predictive and prognosis value of PIK3CA mutations in HER2-positive breast cancer treated with TKIs. Methods: The following databases were searched from inception to July 2022: Medline, Embase and the Cochrane Library. Abstracts from conferences were also reviewed for inclusion. The critical information was extracted from eligible studies. Results: A total of 16 reports including 17 studies were assessed for eligibility, enrolling 1706 patients. Ten studies including 902 patients were in the neoadjuvant setting, the pCR rate is significantly higher in PIK3CA wild-type (WT) patients than in mutated-type (MT) patients (OR = 0.45; 95% CI: 0.31-0.65; P&amp;lt; 0.001). Seven studies including 804 patients were in the metastatic setting, the pooled objective response rate (ORR) is significantly higher in PIK3CA WT patients than in MT patients (OR = 0.40; 95% CI: 0.23-0.70; P = 0.001), and similarly, the clinical benefit rate (CBR) in WT patients is also higher (OR = 0.43; 95% CI: 0.19-0.98; P=0.045). A total of 4 metastasis studies reported progression free survival (PFS), and 2 of them reported overall survival (OS), revealing a marginally significant relationship between PIK3CA mutation and worse PFS (HR = 0.82; 95% CI: 0.67-1.00; P=0.052) and OS (HR=0.63, 95%CI:0.39-1.02; P=0.062). No evidence of publication bias was found in both the neoadjuvant setting and metastatic setting. Conclusion: Our findings indicate that PIK3CA mutations is significantly associated with a lower rate of pCR when treated with TKI-containing regimens in neoadjuvant chemotherapy of early-stage HER2-positive breast cancer, and is significantly associated with lower ORR and CBR in metastatic HER2-positive breast cancer. Citation Format: Qiyun Shi, Juncheng Xuhong, Hao Tian, Yi Zhang, Jun Jiang, Xiaowei Qi. Predictive and prognosis value of PIK3CA mutations in HER2-positive breast cancer treated with tyrosine kinase inhibitors (TKIs): a systemic review and meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-52.

Efficacy and Safety of Dual-Targeting Chimeric Antigen Receptor-T Therapy for Relapsed or Refractory B Cell Lymphoid Malignancies: A Systematic Review and Meta-Analysis.

Dual-targeting chimeric antigen receptor (CAR)-T cell therapy has been proposed as a potential solution for overcoming antigen escape during anti-CD19 CAR-T treatment. We performed this systematic review and meta-analysis to investigate the efficacy and safety of this novel treatment in patients with B cell non-Hodgkin lymphoma (B-NHL) and B cell acute lymphoblastic leukemia (B-ALL). We systematically searched relevant literature based on databases (PubMed, Web of Science, Embase and Cochrane) and conference abstracts. The primary outcomes measured were the best objective response rate (ORR) or complete response (CR), 12-month overall survival (OS) and progression-free survival (PFS), cytokine release syndrome (CRS), and neurotoxicity. Fifteen registered prospective open-label clinical trials were included. Among the 260 patients with B-NHL, the pooled best ORR and CR were 77% (95% confidence interval [CI]: 0.71-0.82) and 52% (95% CI: 0.40-0.63), respectively, and the pooled 12-month PFS and OS were 54.0% (95% CI: 0.47-0.61) and 66.0% (95% CI: 0.56-0.77), respectively. In the 159 patients with B-ALL, the combined best CR was observed to be 92% (95% CI: 0.82-0.99) and the pooled 12-month PFS and OS were 65.0% (95% CI: 0.51-0.77) and 73.0% (95% CI: 0.56-0.92), respectively. Moreover, in B-NHL patients, grade ≥3 CRS was observed in 14.0% (95% CI: 0.04-0.29) of these patients, and 5.0% (95% CI: 0.02-0.08) showed grade ≥3 neurotoxicity; in the case of B-ALL patients, grade ≥3 CRS and neurotoxicity occurred in 11.0% (95% CI: 0.04-0.19) and 2.0% (95% CI: 0.00-0.06), respectively. This study demonstrates the safety and clinical efficacy of dual-targeting CAR-T cell therapies in B cell malignancies. Further, well-designed randomized controlled trials are required to establish the role of dual-targeting CAR-T cell therapy in patients with B cell malignancies.

Immunotherapy and tumor mutational burden in cancer patients with liver metastases: A meta and real word cohort analysis.

The predictive effects of liver metastases for immune-checkpoint inhibitors (ICIs) and the relationship between tumor mutational burden (TMB) and liver metastases (LM) remain unclear. A systematic review and meta-analysis were conducted to explore the heterogeneity of ICIs efficacy between patients with or without LM. A pan-cancer cohort of 1,661 patients who received ICIs was downloaded and analyzed to assess the association between TMB and LM. Of 21053 studies identified in our search, eight single-arm studies and 24 randomized controlled trials were included. Overall, 17957 patients with advanced or metastatic cancers (4805 patients (26.8%) with LM and 13151 patients (73.2%) without LM) were enrolled. The pooled objective response rate (ORR) was 8.5% (95% CI 4%-13%) in the LM group versus 21% (95% CI 16%-21%) in the non-LM group. The pooled hazard ratio (HR) for death was 0.85 (95% CI 0.80-0.90) in the LM group treated with ICIs compared with the standard of care. In patients without LM who were treated with ICIs, the pooled HR for death was 0.78 (95% CI 0.73-0.82) compared with the standard of care. The difference in efficacy between patients with or without LM treated with ICIs was significant (p=0.04). Pan-cancer analysis revealed that the TMB-high rate was 10.8% in liver metastatic lesions versus 21.4% in other metastatic lesions (p=0.004). In addition, TMB was also significantly associated with OS as a binary cutoff (p=0.05) and was an independent prognostic variable (HR=0.98, P=0.047) as a continuous variable in patients with LM. In patients with LM, the efficacy of immunotherapy was attenuated, but TMB-high could predict better survival outcomes.

Conventional and drug-eluting beads transarterial chemoembolization in patients with unresectable intrahepatic cholangiocarcinoma: a systematic review and pooled analysis.

Patients with unresectable intrahepatic cholangiocarcinoma (ICC) have poor survival. Conventional transarterial chemoembolization (c-TACE) and drug-eluting beads transarterial chemoembolization (DEB-TACE) are two treatment options for ICC, and this systematic review describes the efficacy of each of these modalities for unresectable ICC to guide clinical practice. A literature search was performed in PubMed, Web of Science, and Embase databases regarding transhepatic arterial chemoembolization for intrahepatic cholangiocarcinoma. The Newcastle-Ottawa quality assessment Scale (NOS) was used to assess the risk of bias. Tumor response, disease control, and 1-, 2-, 3-year overall survival rate were pooled for estimation. The number of initial search results was 1035, and 19 articles met the inclusion criteria for this study after the screening. A total of 23 study cohorts and 1091 patients were provided. The pooled objective response rate (ORR) for c-TACE and DEB-TACE treating ICC was 29.4% (95% CI 11.6-50.8%) and 51.2% (95% CI 30.6-71.7%), respectively; disease control rate (DCR) was 72.8% (95% CI 55.6-87.3%) and 88.7% (95% CI 78.8-96.2%), respectively. The pooled survival rate at 1 year, 2 year, and 3 year was 49.7% (95% CI 39.1-60.3%), 24.0% (95% CI 12.6-37.3%), and 23.5% (95% CI 11.1-38.7%) for c-TACE; 58.6% (95% CI 44.2-72.3%), 26.7% (95% CI 18.1-36.3%), and 16.2% (95% CI 6.0-29.4%) for DEB-TACE. The descriptive analysis suggested that DEB-TACE treatment for ICC may have better tumor response and disease control rates than c-TACE treatment, but the impact on overall survival was not demonstrated significantly by DEB-TACE treatment.

Efficacy and Safety of PD-1/PD-L1 Inhibitors in Advanced Hepatocellular Carcinoma: A Systematic Review and Meta-analysis.

Programmed cell death1 (PD-1) and programmed cell death ligand1 (PD-L1) inhibitors have been increasingly employed for the treatment of various cancers in clinical practice. This study aimed to systematically evaluate the efficacy and safety of PD-1/PD-L1 inhibitors for advanced hepatocellular carcinoma (HCC). PubMed, EMBASE, Cochrane library, Web of Science, and Abstracts of American Society of Clinical Oncology proceedings databases were searched. Objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), median overall survival (OS), and incidence of adverse events (AEs) and drug withdrawal were pooled. Odds ratio (OR) and hazard ratio (HR) were calculated to analyze the difference in the ORR, DCR, PFS, and OS between groups. Among the 14,902 initially identified papers, 98 studies regarding use of PD-1/PD-L1 inhibitors in advanced HCC were included. Based on different criteria of response in solid tumors, the pooled ORR, DCR, and median PFS was 16-36%, 54-74%, and 4.5-6.8months, respectively. The pooled median OS was 11.9months. Compared to multitarget tyrosine kinase inhibitors (TKIs), PD-1/PD-L1 inhibitors monotherapy significantly increased ORR (OR 2.73, P < 0.00001) and OS (HR 0.97, P = 0.05), and PD-1/PD-L1 inhibitors combined with TKIs significantly increased ORR (OR 3.17, P < 0.00001), DCR (OR 2.44, P < 0.00001), PFS (HR 0.58, P < 0.00001), and OS (HR 0.58, P < 0.00001). The pooled incidence of all-grade AEs, grade ≥ 3 AEs, and drug withdrawal was 71%, 25%, and 7%, respectively. On the basis of the present systematic review and meta-analysis, PD-1/PD-L1 inhibitors should be the preferred treatment choice for advanced HCC owing to their higher antitumor effect and improved outcomes.

Efficacy and safety of brigatinib in ALK-positive non-small cell lung cancer treatment: A systematic review and meta-analysis

Brigatinib is a central nervous system-active second-generation anaplastic lymphoma kinase (ALK) inhibitor that targets a broad range of ALK rearrangements in patients with non-small cell lung cancer (NSCLC). The current study aimed to analyze the pooled effects and adverse events of brigatinib in patients with ALK-positive NSCLC. The pooled estimates and 95% confidence intervals (CI) were calculated with DerSimonian-Laird method and the random effect model. The pooled objective response rate (ORR) and disease control rate (DCR) of brigatinib were 64% (95% CI 45%-83%) and 88% (95% CI 80%-96%), respectively. The pooled mPFS was 10.52 months (95% CI 7.66-13.37). In the subgroup analyses by treatment line, the highest mPFS was reached in first-line treatment (24.00 months, 95% CI 18.40-43.20), followed by post-crizotinib second-line treatment (mPFS=16.26 months, 95% CI 12.87-19.65), and second-line with any prior ALK tyrosine kinase inhibitors (mPFS=12.96 months, 95% CI 11.14-14.78). Among patients with any baseline brain metastases, the pooled intracranial ORR (iORR) was estimated as 54% (95% CI 35%-73%) for any treatment line, and 60% (95% CI 39%-81%) for first-line treatment. Intracranial PFS (iPFS) reached 19.26 months (95% CI 14.82-23.70) in patients with any baseline brain metastases. Creatine phosphokinase (CPK) increased (44%, 95% CI 26%-63%), diarrhea (37%, 95% CI 27%-48%), and nausea (28%, 95% CI 17%-39%) of any grade were the most common adverse events. Brigatinibis effective in the treatment of patients with ALK-positive NSCLC, particularly showingrobust intracranial PFS. Brigatinib used as first-line treatment yielded superior PFS compared with brigatinib used as other treatment lines. These results suggested a benefit of using brigatinib earlier in the patient's management. All adverse events are manageable, with CPK increased and gastrointestinal reactions found to be the most common types. https://inplasy.com/inplasy-2022-3-0142/, identifier (INPLASY202230141).

Efficacy and safety of triplet chemotherapy plus anti-EGFR agents in metastatic colorectal cancer: a systematic review and meta-analysis

BackgroundTo date, the optimal treatment for potentially resectable metastatic colorectal cancer (mCRC) patients has yet to be determined. Encouraging results have been reported in studies exploring the efficacy of triplet chemotherapy plus anti-epidermal growth factor receptor (anti-EGFR) target agents. Thus, we conducted a meta-analysis to evaluate the efficacy and safety of triplet chemotherapy plus anti-EGFR target agents.MethodsWe systematically searched the PubMed, Embase, and Web of Science databases from December 2004 to October 2021 for studies examining the efficacy of triplet chemotherapy plus anti-EGFR target agents in mCRC patients. The primary outcomes were the objective response rate (ORR) and R0 resection rate (R0RR), and the secondary outcomes were median progression-free survival (mPFS), median overall survival (mOS), and toxicity. Data were analyzed with R software 4.1.2.ResultsFourteen studies comprising 762 patients with mCRC were included in this meta-analysis. Analysis with a random effects model revealed that after treatment with triplet chemotherapy plus anti-EGFR target agents, the pooled ORR was 82% (95% CI= 76–88%, I2= 76%), and the pooled R0RR of colorectal liver metastasis (CLM) was 59% (95% CI= 49–68%, I2= 60%). The mPFS ranged from 9.5 to 17.8 months, and the mOS ranged from 24.7 to 62.5 months. A total of 648 grade 3 or 4 adverse events were reported; the most commonly reported events were diarrhea (174/648), neutropenia (157/648), and skin toxicity (95/648), which had pooled prevalence rates of 29% (95% CI= 20–39%, I2= 84%), 28% (95% CI= 20–37%, I2= 77%), and 17% (95% CI= 11–24%, I2= 66%), respectively.ConclusionsTriplet chemotherapy plus anti-EGFR agents therapy seems to be capable of increasing the ORR of mCRC patients and the R0RR of CLM patients. The toxicity of this treatment is manageable. High-quality randomized controlled trial (RCT) studies are required for further validation.

Efficacy and safety of EGFR inhibitors and radiotherapy in locally advanced non-small-cell lung cancer: a meta-analysis.

Aim: To assess the efficacy and safety of EGFR inhibitors combined with (chemo)radiotherapy in unresectable, locally advanced non-small-cell lung cancer. Materials & methods: A systematic review and meta-analysis of prospective trials was performed. Results: Twenty-eight studies of 1640 patients were included. In patients harboring EGFR-sensitive mutations, the pooled objective response rate, 1-year overall survival rate and 1-year progression-free survival rate of EGFR-TKIs+ (chemo)radiotherapy were 0.803, 0.766 and 0.554, respectively. Compared with chemoradiotherapy, the addition of EGFR inhibitors did not significantly increase the risk of grade ≥3 pneumonitis and esophagitis. Conclusion: EGFR-tyrosine kinase inhibitors combined with (chemo)radiotherapy are tolerable and the clinical benefit is promising, especially in patients with EGFR-sensitive mutations.