Immunotherapy change overcomes acquired resistance after chemo-immunotherapy in unresectable biliary tract cancer

BackgroundThe SITC Immunotherapy Resistance Taskforce recently defined primary and secondary resistance to anti-PD-1 therapy,1 yet there is little data that compares these two scenarios. In particular, detailed radiological dynamics of...

Background: The molecular mechanisms underlying primary versus acquired resistance to anti-PD-1/L1 antibodies have not been comprehensively evaluated across different tumor types. Methods: The Immune Resistance Interrogation Study (IRIS; NCT04243720) is a prospective, investigator-initiated study at the Princess Margaret Cancer Centre, aimed to perform extensive multi-omic characterization of solid tumors with primary resistance (disease progression on first imaging; or stable disease <6 months) versus acquired resistance (partial or complete response; or stable disease ≥6 months) to antiPD-1/L1 agents. A one-time fresh tumor biopsy is collected from patients (pts) who have progressed on anti-PD1/L1 antibody-based treatment as their most recent line of therapy; liquid biopsy or archived FFPE tissue is allowed as alternates when fresh biopsy is insufficient. NGS was performed using Foundation One (324 genes) or Foundation Liquid (309 genes) panels. Frequencies of disrupted genes and variants were compared in pts with primary versus acquired resistance using Fisher’s exact test. The planned samples size of IRIS is 100 pts. Results: Among the first 35 pts enrolled, 22 (63%) had primary resistance and 13 (37%) had acquired resistance. The most common diagnosis was melanoma (17 pts; 49%); followed by head and neck squamous cell carcinoma (13 pts; 37%); endometrial cancer (2 pts; 6%); pleural mesothelioma, gastroesophageal junction and colorectal cancer (1 pt each; 3%). Foundation One was performed in 23 pts (66%), 22 of them (63%) had biopsies with sufficient quality for NGS, and 1 (3%) had the analysis performed using archival FFPE tissue. The remaining 12 pts (34%) had Foundation Liquid testing done using liquid biopsy. Thirty-three pts (94%) had at least one oncogenic alteration. Genes most frequently altered included: TP53 in 16 patients (46%), TERT promoter in 12 pts (34%), CDKN2A in 9 pts (26%), PIK3CA in 6 pts (17%), and PTEN in 5 pts (14%). At the variant level, the most frequent alterations were: TERT promoter -146C>T mutation in 6 patients (17%), followed by TERT promoter -124C>T mutation in 5 patients (14%), FGF19/FGF4/FGF3 and CCND1 amplifications in 4 pts each (11%), and MDM2 amplification, CDK4 amplification and CDKN2A loss, detected in 3 pts each (9%). Pts with acquired resistance had a higher frequency of TP53 mutations (9/13 = 69%) compared to primary resistance pts (7/22 = 32%), p=0.04; however this was not significant when corrected for multiple testing. Interestingly, amplifications in CDK4, CCND1, FGF 19/FGF 3/FGF 4, MDM2 and mutations in NF1 were only identified in pts with primary resistant tumors. Conclusions: No significant differences in disrupted genes and variants were observed in the current analysis. However, this can be due to the small number of pts analyzed thus far. Accrual to this study is ongoing. A comparison of alterations in oncogenic pathways is planned to further define the genomic landscape of pts with primary versus acquired resistance to anti-PD1/PDL1 blockade. Citation Format: Sofia Genta, Farnoosh Abbas Aghababazadeh, Ming S Tsao, Aaron R Hansen, Marcus O Butler, Albiruni R Razak, Philippe L Bedard, Ben X Wang, Pugh J Trevor, Sevan Hakgor, Jeffrey Woo, Benjamin Haibe-Kains, Lillian L Siu, Anna Spreafico. Immune resistance interrogation study (IRIS): Initial report of next generation sequencing (NGS) results in patients with primary versus acquired resistance to anti-PD1/L1 antibodies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA021.

Resistance limits the efficacy and durability of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC). Therefore, we conducted a retrospective cohort study to investigate the outcomes and characteristics of HCC patients with resistance to immunotherapy. Patients with HCC who have received ICIs at Eastern Hepatobiliary Surgery Hospital between 2016 and 2021 were retrospectively screened and divided into primary resistance, secondary resistance, and durable response group. Time to progression (TTP), overall survival (OS), subsequent management and post-progression survival (PPS) were analyzed. Of 496 patients included, 229 (46.2%) and 141 (28.4%) patients developed primary and secondary resistance, and 126 (25.4%) patients achieved a durable response, the median TTP was 2.83 [2.56–3.09] months, 11.93 [10.45–13.40] months, and not reached, respectively, whereas the median OS was 12.83 [10.36–15.30] months, 31.53 [28.09–34.97] and not reached, respectively. Multivariate logistic regression revealed that Child–Pugh score, BCLC stage, and combined systemic therapies (ICI plus bevacizumab or lenvatinib versus ICI monotherapy) were independently associated with primary resistance, and only combined systemic therapies (ICI plus bevacizumab versus ICI monotherapy) were independently associated with secondary resistance. AFP levels were independently associated with PPS in patients with primary resistance, while post-progression therapies (ICI-based therapies versus others) were independently associated with PPS in patients with resistance. The risk of resistance was notably lower in patients receiving the combination of ICI plus bevacizumab. High AFP levels were associated with the survival of patients with primary resistance. ICI-based maintenance therapy after resistance may provide a significant survival advantage for HCC patients.

9619 Background : Toll like receptor 3 (TLR3) is known to be expressed by myeloid dendritic cells (DC) and to induce their maturation following binding with double stranded RNA (dsRNA) or its synthetic homologues polyAU and polyI:C. Several clinical trials have reported that injection of dsRNA is associated with survival benefit in cancer patients. In the present study, we have asked whether dsRNA could act directly on tumor cells through TLR3. Patients and methods : 300 patients with early breast cancer have been included from 1972 to 1979 in a randomized trial comparing post-operative administration of polyAU with no treatment. Results have been reported that showed a trend for a survival benefit in patients with involved axillary lymph nodes (n=200). Tumor biopsies from these patients were stained with TLR3-specific mAb and correlation between TLR3 expression and polyAU efficacy was determined. To investigate directly the effects of dsRNA, both freshly isolated breast tumor cells and cancer cell lines were cultured with polyI:C, and apoptosis was measured. The involvement of TLR3 in cell response was established by TLR3 RNA interference. Results : 182 tumor samples (91%) were available from the 200 pTxN+M0 patients included in this randomized trial. TLR3 was strongly expressed by tumor cells in 18 patients (10%). Table 1 reports the 20-year survival rates according to treatment and TLR3 expression. In vitro studies showed that breast cancer cell lines can express TLR3, and that dsRNA can induce up to 80% apoptosis in TLR3+ tumor cell lines within 48h of culture. This pro-apoptotic effect of double stranded RNA was specifically abolished by RNA interference for TLR3. Conclusion : These data suggest that: i. TLR3 is expressed by breast cancer cells in a subset of patients, ii. its activation by dsRNA could lead to tumor cell apoptosis in vitro and survival benefit in patients with TLR3+ tumors. No significant financial relationships to disclose.

9619 Background : Toll like receptor 3 (TLR3) is known to be expressed by myeloid dendritic cells (DC) and to induce their maturation following binding with double stranded RNA (dsRNA) or its synthetic homologues polyAU and polyI:C. Several clinical trials have reported that injection of dsRNA is associated with survival benefit in cancer patients. In the present study, we have asked whether dsRNA could act directly on tumor cells through TLR3. Patients and methods : 300 patients with early breast cancer have been included from 1972 to 1979 in a randomized trial comparing post-operative administration of polyAU with no treatment. Results have been reported that showed a trend for a survival benefit in patients with involved axillary lymph nodes (n=200). Tumor biopsies from these patients were stained with TLR3-specific mAb and correlation between TLR3 expression and polyAU efficacy was determined. To investigate directly the effects of dsRNA, both freshly isolated breast tumor cells and cancer cell lines were cultured with polyI:C, and apoptosis was measured. The involvement of TLR3 in cell response was established by TLR3 RNA interference. Results : 182 tumor samples (91%) were available from the 200 pTxN+M0 patients included in this randomized trial. TLR3 was strongly expressed by tumor cells in 18 patients (10%). Table 1 reports the 20-year survival rates according to treatment and TLR3 expression. In vitro studies showed that breast cancer cell lines can express TLR3, and that dsRNA can induce up to 80% apoptosis in TLR3+ tumor cell lines within 48h of culture. This pro-apoptotic effect of double stranded RNA was specifically abolished by RNA interference for TLR3. Conclusion : These data suggest that: i. TLR3 is expressed by breast cancer cells in a subset of patients, ii. its activation by dsRNA could lead to tumor cell apoptosis in vitro and survival benefit in patients with TLR3+ tumors. No significant financial relationships to disclose.

Background: Why some patients fail or have short lived response to immune checkpoint blockade (ICB) immunotherapy remains largely unknown. While baseline molecular assessments have provided clues to prognostic factors, insights into resistance drivers remains elusive. This is partially due to the difficulty in getting access to post progression samples from patients that were either primary resistant or developed acquired resistance after an initial response to ICB. Thus, the tumor-intrinsic and -extrinsic features that are selected for during progression and potentially drive primary and acquired resistance to immunotherapy remain underexplored. Methods: To compare clinical features and immunogenomic drivers of acquired and primary resistance to ICB across major cancers, we analysed and annotated de-identified patient records in the Tempus real-world database. We built an immuno-oncology cohort consisting of >2500 multimodal (DNA, RNA and clinical outcome data) pre-treatment baseline with >1500 post-treatment tumour biopsy samples from mainly NSCLC, TNBC, HNC and Bladder cancer patients. We used bulk RNA-seq data to estimate activation of the hallmark oncogenic pathways and immune cell composition and used panel DNA-seq data (>500 genes) to quantify mutation selection at the gene and pathway levels using dndscv. Results: Compared to acquired, primary resistant patients tended to have a higher observation of liver lesions at progression. Post-ICB, acquired resistant NSCLC and HNC patients showed a significantly inflamed tumour microenvironment (TME) characterised by higher estimation of infiltration of T cells and myeloid cells and higher activation of interferon gamma (IFNg) signalling as compared to primary resistant patients. In addition, in post-ICB acquired resistance in NSCLC we observed selection for mutations in genes involved in known immunomodulatory pathways, including loss-of-function mutations in B2M. Consistently, acquired resistance patients showed stronger selection for mutations in Hedgehog and Notch pathways as compared to primary resistance patients across NSCLC, HNC and TNBC post-ICB. Conclusions: Acquired and primary ICB resistant patients have distinct clinical and molecular features at progression. Their tumours’ TME is fundamentally different with acquired resistance TMEs being infiltrated with immune cells albeit escaped post progression. In addition, ICB selects mutations that potentially activate pathways such as Notch and Hedgehog. This multi-modal Real-World Data with post therapy biopsies has given insights for patient selection strategies and provides rational into combination treatment options for acquired resistant patients. Citation Format: Mohamed Reda Keddar, Sebastian Carrasco Pro, Kathleen Burke, Ana Camelo Stewart, Mark Cobbold, Ross Stewart, Sajan Khosla, Ben Sidders, Scott Hammond, Douglas C. Palmer, Jonathan Dry, Martin L. Miller. Multimodal real world data reveals immunogenomic drivers of acquired and primary resistance to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5100.

For decades, stratification criteria for first-line clinical studies have been highly uniform. However, there is no principle or consensus for restratification after systemic treatment progression based on immune checkpoint inhibitors (ICIs). The aim of this study was to assess the patterns of disease progression in patients with advanced hepatocellular carcinoma (HCC) who are not eligible for surgical intervention, following the use of immune checkpoint inhibitors. This is a retrospective study that involved patients with inoperable China liver stage (CNLC) IIIa and/or IIIb. The patients were treated at eight centers across China between January 2017 and October 2022. All patients received at least two cycles of first-line treatment containing immune checkpoint inhibitors. The patterns of disease progression were assessed using RECIST criteria 1.1. Different progression modes have been identified based on the characteristics of imaging progress. The study's main outcome measures were post-progression survival (PPS) and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method to compare the difference among the four groups. Subgroup analysis was conducted to compare the efficacy of different immunotherapy combinations. Variations in the efficacy of immunotherapy have also been noted across patient groups exhibiting alpha-fetoprotein (AFP) levels equal to or exceeding 400ng/mL, in contrast to those with AFP levels below 400ng/mL. The study has identified four distinct patterns of progress, namely p-IIb, p-IIIa, p-IIIb, and p-IIIc. Diverse patterns of progress demonstrate notable variations in both PPS and OS. The group p-IIb had the longest PPS of 12.7m (95% 9.3-16.1) and OS 19.6m (95% 15.6-23.5), the remaining groups exhibited p-IIIb at PPS 10.5 months (95%CI: 7.9-13.1) and OS 19.2 months (95%CI 15.1-23.3). Similarly, p-IIIc at PPS 5.7 months (95%CI: 4.2-7.2) and OS 11.0 months (95%CI 9.0-12.9), while p-IIIa at PPS 3.4 months (95%CI: 2.7-4.1) and OS 8.2 months (95%CI 6.8-9.5) were also seen. Additional stratified analysis was conducted and showed there were no differences of immunotherapy alone or in combination in OS (HR= 0.92, 95%CI: 0.59-1.43, P=0.68) and PPS (HR= 0.88, 95%CI: 0.57-1.36, P=0.54); there was no significant difference in PPS (HR=0.79, 95% CI: 0.55-1.12, P=0.15) and OS (HR=0.86, 95% CI: 0.61-1.24, P=0.39) for patients with AFP levels at or over 400ng/mL. However, it was observed that patients with AFP levels above 400ng/mL experienced a shorter median progression of PPS (8.0 months vs. 5.0 months) after undergoing immunotherapy. In this investigation of advanced hepatocellular carcinoma among Chinese patients treated with immune checkpoint inhibitors, we identified four distinct progression patterns (p-IIb, p-IIIa, p-IIIb and p-IIIc) that showed significant differences in PPS and OS. These findings demonstrate the heterogeneity of disease progression and prognosis after immunotherapy failure. Further validation in large cohorts is necessary to develop prognostic models that integrate distinct progression patterns to guide subsequent treatment decisions. Additionally, post-immunotherapy progression in patients with AFP levels ≥400ng/mL indicates a shortened median PPS. These findings provide valuable insights for future personalized treatment decisions.

BackgroundWhy some patients fail or have short lived response to immune checkpoint blockade (ICB) immunotherapy remains largely unknown. While baseline molecular assessments have provided clues to prognostic factors, insights into...

e16209 Background: Immunotherapy have revolutionized the therapeutic landscape of hepatocellular carcinoma (HCC). However, clinical features affecting immune resistance remain largely unknown. This retrospective cohort study aims to investigate the outcomes and characteristics of pts with resistance to immunotherapy in HCC. Methods: Pts with HCC who received immune checkpoint inhibitors (ICIs) of PD-1/PD-L1 antibodies at Eastern Hepatobiliary Surgery Hospital between 2016 and 2021 were retrospectively enrolled and screened for eligibility. Recommended by the Society for Immunotherapy of Cancer (SITC), primary resistance was defined as when pts were exposed to ICIs therapy for at least 6 weeks and with the best overall response (BOR) of PD or SD for less than 6 months. Secondary resistance was defined as pts having disease progression after the initial objective response (CR/PR) or SD for more than 6 months. The durable response group consists of pts with the durable response (CR, PR, or SD) for more than 6 months without progression at data cutoff. Time to progression (TTP), overall survival (OS) and clinicopathological features of HCC pts were compared between groups. Subsequent management after resistance and post-progression survival (PPS) were also analyzed. Results: Of 496 pts included, 229 (46.2%) and 141 (28.4%) pts developed primary resistance and secondary resistance, and 126 (25.4%) pts achieved a durable response. The median follow-up was 22.8 months. For pts with primary resistance, secondary resistance, and durable response, the median TTP was 2.83 [2.56-3.09] months, 11.93 [10.45-13.40] months, and not reached, respectively. Whereas the median OS was 12.83 [10.36-15.30] months, 31.53 [28.09-34.97] months and not reached, respectively. Multivariate logistic regression revealed that the Child-Pugh score (Child-Pugh B versus A, OR 3.28 [1.51-7.13], p= 0.003), BCLC stage (BCLC B versus A, OR 3.55 [1.70-7.43], p= 0.001; BCLC C versus A, OR 2.88 [1.47-5.65], p= 0.002), and combinational therapies (ICIs+bevacizumab versus monotherapy, OR 0.14 [0.04-0.51], p= 0.003; ICIs plus lenvatinib+monotherapy, OR 0.43 [0.26-0.72], p= 0.001) were independently associated with primary resistance, and only the combination of ICIs plus bevacizumab (ICIs+bevacizumab versus monotherapy, OR 0.10 [0.01-0.52], p= 0.007) was independently associated with secondary resistance. AFP levels and post-progression therapies were independently associated with PPS in pts with primary resistance, while post-progression therapies were independently associated with PPS in pts with secondary resistance. Conclusions: Risk for resistance was significantly lower among pts who received ICIs plus bevacizumab.High AFP levels independently predict the survival of pts after primary resistance to immunotherapy. ICI-based maintenance therapy after resistance may provide a significant survival advantage for HCC pts.

UK Third National Colorectal Cancer Consensus Meeting 2008

The last decade has brought significant advances in the development of molecularly targeted therapies for treatment of a variety of human malignancies. In contrast to other solid tumors, however, the impact of novel therapeutic strategies on clinical outcomes in patients with pancreas adenocarcinoma (PAC) has been limited to date. Gemcitabine was established as a standard of care for treatment of advanced PAC in 1997 based on an observed improvement in clinical benefit as adjudicated principally by pain scores and analgesic consumption, and demonstration of an overall survival (OS) benefit in a randomized comparison with 5-fluorouracil (5-FU). Since then, multiple agents targeting oncogenic signaling pathways and mediators of angiogenesis have failed to improve outcomes in phase III clinical trials when compared with gemcitabine monotherapy. An exception to this is the anti-epidermal growth factor receptor therapy erlotinib, which yielded a survival benefit in patients with advanced disease in combination with gemcitabine compared with gemcitabine alone, although this was a marginal incremental improvement for which the clinical significant has been heavily debated. More recently, the most significant therapeutic advance in PAC has come from the combination of several cytotoxic agents; infusional 5-FU, irinotecan and oxaliplatin. This combination chemotherapy regimen, known as FOLFIRINOX, improved survival in patients with an excellent functional status and stage IV disease by 4.3 months compared with gemcitabine alone. This improvement in survival did come at the cost expectedly of a significant increase in toxicities, including gastrointestinal and hematologic particularly. Other gemcitabine-based combination chemotherapy regimens including gemcitabine and platinum analogs and gemcitabine and capecitabine have consistently shown an increased response rate but no OS benefit in individual trials; albeit pooled and meta-analyses have indicated a survival benefit in good performance status patient for both these cytotoxic combinations. Accordingly, the 5-year survival for patients with PAC remains <5%, with an annual disease-specific mortality which approaches the incidence. The challenge remains therefore, to develop more effective systemic therapies against this challenging malignancy. Recent progress toward understanding the genetic events in the development of PAC, in combination with advances in the field of pharmacogenomics offer hope that we may build on achievements to-date to develop more effective therapeutic strategies for PAC in years to come.

BackgroundAlthough the Society for Immunotherapy of Cancer (SITC) Immunotherapy Resistance Taskforce recently defined primary and secondary resistance to anti-programmed cell death protein 1 (anti-PD-1) therapy, there is lack of real-world...

2515 Background: The gut microbiome modifies response to ICI treatment. Despite durable response rates seen with ICI, most pts do not benefit from treatment (primary resistance) or have only a period of disease control (acquired resistance). The Immune Resistance Interrogation Study (IRIS, NCT03702309) is a prospective pan-cancer study that aims at characterizing ICI-resistant disease through multiomic and gut microbial composition profiling. Herein we compare the gut microbial diversity of pts with PR vs AR to PD-1/PD-L1 based treatment as part of the wider IRIS framework. Methods: Patients who progressed after anti-PD1/PD-L1-based ICI were classified into 2 groups. Acquired resistance (AR): complete response (CR), partial response (PR) or stable disease (SD) for ≥6 months (m) with subsequent (PD) or PD after ≥3m from last dose of adjuvant ICI; or primary resistance (PR): PD at first imaging, SD but progressed ≤6m or progression ≤3m from last dose of adjuvant ICI. Stool samples were collected at time of PD and underwent DNA extraction and metagenomic sequencing. Species-level Shannon diversity indices were calculated and compared using unpaired Wilcoxon test. Principal component analysis (PCA) of Bray-Curtis dissimilarity indices was performed to assess differences in taxonomic composition. Results: Stool samples from 62 pts (PR n=38; AR n=24) were evaluated. Tumor types were melanoma n=37 (60%), head and neck n=17/62 (27%), gastrointestinal n=3/62 (5%), gynaecological n=2/62 (3%) and other n=3/61 (5%). Most pts n=59/62 (95%) were treated with palliative intent, and n= 3/62 (5%) with adjuvant therapy. Anti-PD-1/PD-L1 monotherapy was received by 32/62 (52%) pts and n=30/62 (48%) received combination anti-PD-1/PD-L1 with either anti-CTLA-4 inhibition, experimental immunotherapy, chemotherapy, or targeted treatment. The median Shannon diversity index was similar between pts with PR (median: 3.5; range: 2.5 - 4.3) vs AR (median: 3.4; range: 0.9 – 3.9; p = 0.7). There were no differences in composition by group by PCA of Bray-Curtis dissimilarity indices. Abundance testing did not reveal any differentially abundant species between pts with AR vs PR while controlling for antibiotic use within 1m of sampling and type of treatment. No taxa were significantly different between AR and PR; top taxa per group are shown. Conclusions: Primary analysis showed no significant differences in gut microbial composition between primary vs acquired resistance to ICI. Comparative analysis between ICI-resistance samples and ICI-naïve samples from historical patient cohorts is underway. These results will be collated with other analyses from IRIS to create a multi-modal characterisation of ICI resistance. Clinical trial information: NCT03702309 . [Table: see text]

Alectinib confers a pronounced survival benefit in patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status. Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases. We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement-positive non-small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long-term survival benefit in such patients. Eighteen patients with ALK rearrangement-positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study. The median follow-up time for all patients was 27.3 months. The median progression-free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1-30.8 months), and the median survival time (MST) and the 3-year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8-64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886). Alectinib showed a pronounced survival benefit for patients with ALK rearrangement-positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated.

Background: Glioblastoma multiforme (GBM) inevitably recurs, but no standard regimen has been established for recurrent patients. Reoperation at recurrence alleviates mass effects, and the survival benefit has been reported in many studies. However, in most studies, the effect of reoperation timing on survival benefit was ignored. The aim of this meta-analysis was to investigate whether reoperation provided similar survival benefits in recurrent GBM patients when it was analyzed as a fixed or time-dependent covariate.Methods: A systematic literature search of PubMed, EMBASE, and Cochrane databases was performed to identify original articles that evaluated the associations between reoperation and prognosis in recurrent GBM patients.Results: Twenty-one articles involving 8,630 patients were included. When reoperation was considered as a fixed covariate, it was associated with better overall survival (OS) and post-progression survival (PPS) (OS: HR = 0.66, 95% CI 0.61-0.71, p < 0.001, I2 = 0%; PPS: HR = 0.70, 95% CI 0.57–0.88, p < 0.01, I2 = 70.2%). However, such a survival benefit was not observed when reoperation was considered as a time-dependent covariate (OS: HR = 2.19, 95% CI 1.47–3.27, p < 0.001; PPS: HR = 0.95, 95% CI 0.82–1.10, p = 0.51, I2 = 0%). The estimate bias caused by ignoring the time-dependent nature of reoperation was further demonstrated by the re-analysis of survival data in three included studies.Conclusions: The timing of reoperation may have an impact on the survival outcome in recurrent GBM patients, and survival benefits of reoperation in recurrent GBM may be overestimated when analyzed as fixed covariates. Proper analysis methodology should be used in future work to confirm the clinical benefits of reoperation.