Progression-free Survival Hazard Ratio Research Articles

Subgroup analyses of the phase 3 CAIRO3 trial: Association of number and total volume of metastases on survival in patients with metastatic colorectal cancer based on a deep-learning automatic segmentation model.

130 Background: Maintenance treatment with capecitabine and bevacizumab after capecitabine, oxaliplatin, and bevacizumab therapy in metastatic colorectal cancer (mCRC) is shown to be effective with observation as an acceptable alternative. Metastatic burden might aid in shared decision-making and the aim of this exploratory analysis is to assess the prognostic and predictive value of number and total volume of metastases in mCRC patients included in the CAIRO3 study. Methods: Patients in the CAIRO3 study with liver and/or lung metastases were included. Every individual liver and lung metastasis was counted and volumes were assessed using deep-learning automatic segmentation software (SAS analytical platform and Philips IntelliSpace). Lymph node metastases were counted manually. Each scan was supervised by a dedicated radiologist. Kaplan-Meier analyses were used to estimate progression-free survival (PFS) and overall survival (OS) using log-rank testing for statistical comparison. Hazard ratios (HR) were estimated using Cox regression models. Results: A total of 156 patients were included with 154 OS events, in which 8198 metastases were identified: 5179 were liver metastases, 2835 lung metastases, and 184 lymph node metastases. Patients had a mean age of 63 years and 67% were male. At randomization, the median number of metastases was 9 and mean total metastatic volume was 116 cm3. Median OS for patients with ≤10 versus >10 metastases was 22.0 months (95%CI: 19.3-29.3) and 14.3 months (95% CI: 11.6-20.9, p-value <0.01), with similar differences for low/high tumor volume. In multivariable analysis number and total volume were independent prognostic markers for PFS and OS, respectively, after adjustment for age, sex, WHO performance score, treatment arm, serum lactate dehydrogenase (LDH) level, site of primary tumor, time to metastases, and treatment response. Benefit of maintenance therapy was most pronounced in patients with ≤10 compared to >10 metastases with a PFS HR of 0.24 (0.12-0.46) compared to 0.52 (0.28-0.96) and OS HR of 0.75 (0.42-1.34) compared to 1.17 (0.66-2.08), demonstrating potential predictive value. Conclusions: Metastatic burden is associated with a poor prognosis in patients with mCRC. Furthermore, patients with limited metastatic disease (1-10 metastases) benefit most from maintenance treatment and this could potentially be a predictive biomarker. [Table: see text]

Efficacy and safety of VEGF/VEGFR inhibitors for platinum-resistant ovarian cancer: a systematic review and meta-analysis of randomized controlled trials

BackgroundAlmost all patients with ovarian cancer will experience relapse and eventually develop platinum-resistant. The poor prognosis and limited treatment options have prompted the search for novel approaches in managing platinum-resistant ovarian cancer (PROC). Therefore, a meta-analysis was conducted to evaluate the efficacy and safety of combination therapy with vascular endothelial growth factor (VEGF) /VEGF receptor (VEGFR) inhibitors for PROC.MethodsA comprehensive search of online databases was conducted to identify randomized clinical trials published until December 31, 2022. Pooled hazard ratios (HR) was calculated for overall survival (OS) and progression-free survival (PFS), while pooled odds ratio (OR) was calculated for objective response rate (ORR) and treatment-related adverse events (TRAEs). Subgroup analysis was further performed to investigate the source of heterogeneity.ResultsIn total, 1097 patients from eight randomized clinical trials were included in this meta-analysis. The pooled HRs of OS (HR = 0.72; 95% CI: 0.62–0.84, p < 0.0001) and PFS (HR = 0.52; 95% CI: 0.45–0.59, p < 0.0001) demonstrated a significant prolongation in the combination group compared to chemotherapy alone for PROC. In addition, combination therapy demonstrated a superior ORR compared to monotherapy (OR = 2.34; 95%CI: 1.27–4.32, p < 0.0001). Subgroup analysis indicated that the combination treatment of VEGF/VEGFR inhibitors and chemotherapy was significantly more effective than monochemotherapy in terms of OS (HR = 0.71; 95% CI: 0.61–0.84, p < 0.0001), PFS (HR = 0.49; 95% CI: 0.42–0.57, p < 0.0001), and ORR (OR = 2.97; 95% CI: 1.89–4.67, p < 0.0001). Although the combination therapy was associated with higher incidences of hypertension, mucositis, proteinuria, diarrhea, and hand-foot syndrome compared to monochemotherapy, these toxicities were manageable and well-tolerated.ConclusionsThe meta-analysis demonstrated that combination therapy with VEGF/VEGFR inhibitors yielded better clinical outcomes for patients with PROC compared to monochemotherapy, especially when combined with chemotherapy. This analysis provides more treatment options for patients with PROC.Systematic review registration[https://www.crd.york.ac.uk/PROSPERO], Prospective Register of Systematic Reviews (PROSPERO), identifier: CRD42023402050.

Immune checkpoint inhibitors plus chemotherapy in first-line endometrial cancer treatment: Still the era of microsatellites?

The combination of immune checkpoint inhibitors (ICIs) plus chemotherapy is currently being tested as the first-line treatment of advanced endometrial. We aimed to evaluate the efficacy and safety of this combination. We performed a meta-analysis of randomized clinical trials. Patients with advanced endometrial carcinoma receiving ICIs plus chemotherapy in the experimental arm, compared with chemotherapy plus placebo in the control arm, were included. We evaluated the progression-free survival (PFS) as an efficacy outcome and the number and grades of adverse events (AEs) for safety. Hazard ratios (HR) for PFS and risk ratios (RR) for AEs, with 95% confidence intervals (CI), were calculated. 1303 patients were treated in the included studies. Adding ICIs to chemotherapy significantly improved PFS in mismatch repair deficient (dMMR-HR 0.29; 95% CI, 0.20-0.42; p < 0.00001) and in mismatch repair proficient (pMMR-HR 0.64; 95% CI, 0.46-0.90; p = 0.01) patients. No difference emerged for all-grades AEs (RR 1.00; p = 0.98), but the risk of ≥G3 AEs was increased in the ICIs + chemotherapy group (RR 1.22; 95% CI, 1.11-1.34; p < 0.0001). Adding ICIs to chemotherapy significantly improves PFS in first-line endometrial cancer, regardless of MMR status.

Unveiling the prognostic significance of malignant ascites in advanced gastrointestinal cancers: a marker of peritoneal carcinomatosis burden.

Ascites is common in advanced gastrointestinal cancers with peritoneal metastases (PM) and negatively impacts patient survival. No study to date has specifically evaluated the relationship between ascites, PM and survival outcomes in metastatic colorectal cancer (mCRC) and metastatic gastric cancer (mGC). This study aims to investigate and elucidate the relationship between malignant ascites, PM and survival outcomes in both mCRC and mGC patients. This is a retrospective analysis of prospectively collected clinical trial data of mCRC and mGC patients with PM. We performed two pooled analyses, firstly of two Italian randomized trials enrolling patients with mCRC eligible for systemic therapy (TRIBE2; VALENTINO), and secondly of gastric cancer and peritoneal metastasis (GCPM) patients who underwent bi-directional therapeutic treatment comprising systemic and peritoneal-directed therapies. Of 900 mCRC patients, 39 (4.3%) had PM with malignant ascites. Compared to the group without PM, median progression-free and overall survival were significantly inferior in the ascites group (hazard ratio (HR) for progression-free survival (PFS) 1.68, 95% confidence interval (CI): 1.21-2.35, p = 0.007; HR for overall survival (OS) 2.14, 95% CI: 1.57-3.01, p < 0.001), but not in the group of PM without ascites (HR for PFS 1.10, 95% CI: 0.91 - 1.34; HR for OS 1.04, 95% CI: 0.84 - 1.30). Of 170 patients with GCPM, those with ascites had higher median Peritoneal Cancer Index scores (23 vs 9, p < 0.001). Median OS was significantly inferior among those with ascites compared to those without (13.0 vs 21.0 months, HR 1.71, 95% CI: 1.16-2.52, p = 0.007). Ascites identifies a subgroup of patients with PM and poor outcomes, for whom tailored research are needed.

Rate of non-metastatic solid tumor progression following critical illness: a prospective cohort study of UK Biobank participants.

To determine whether admission to critical care is associated with subsequent disease progression in patients with non-metastatic solid tumors. This observational cohort study of UK Biobank participants identified those diagnosed with solid tumors and survived hospitalization. Two cohorts were identified based on critical care admission and new metastatic disease as reported at UK Biobank follow-up visits, or primary or secondary care records were compared. Cox proportional hazards analysis was used to account for potential confounders in the multivariate analysis. A total of 1,854 solid tumor patients were identified, of whom 453 (24.4%) experienced critical care admission. Unadjusted rates of metastatic disease and death were higher for the critical care cohort with lower progression-free survival. At five years, 25% of the critical care survivors and 14% of the hospitalized survivors had developed metastatic disease (p < 0.001), with a corresponding progression-free survival rate of 65% versus 81% (p < 0.001). After adjustment for confounders, the hazard ratio for progression-free survival between critical care survivors and the hospitalized cohort was 1.69 (95%CIs 1.31 - 2.18; p < 0.001). Solid tumor patients admitted to the hospital within 2 years of diagnosis had poorer subsequent progression-free survival if they had experienced a critical care admission. This observation was maintained after adjustment for confounding variables.

Albumin-to-D-dimer ratios: A novel prognostic factor for evaluating first-line chemotherapy efficacy in advanced lung adenocarcinoma patients.

The prognosis of advanced lung adenocarcinoma (LUAD) remains unfavorable, with chemotherapy constituting a primary treatment modality. Discerning the efficacy of chemotherapy for advanced LUAD is imperative. Prior investigations have demonstrated the prognostic value of albumin and D-dimer individually for malignancies; however, the predictive capacity of albumin-to-D-dimer ratios (ADR) for advanced LUAD subjected to first-line platinum-based chemotherapy remains unexplored. A cohort of 313 patients with advanced LUAD was retrospectively examined in this study, spanning from January 2017 to January 2021. ADR threshold values were ascertained via receiver operating characteristic analysis, followed by the evaluation of the association between pretreatment ADR and clinicopathological characteristics, disease control rate (DCR), and overall response rate (ORR) pertinent to first-line chemotherapy. Prognostic factors for progression-free survival (PFS) were determined employing Cox univariate and multivariate analyses. Subsequently, survival data were illustrated utilizing the Kaplan-Meier method and scrutinized through the log-rank test across the entire and subgroup populations. ADR demonstrated a superior area under the curve (AUC) value relative to albumin and D-dimer individually and exhibited enhanced prognostic predictive capability compared to albumin-to-fibrinogen ratios (AFR) for advanced LUAD (AUC: 0.805 vs. 0.640, DeLong test: p<0.001). ADR yielded a cut-off value of 16.608. A greater proportion of non-smokers was observed within the high-ADR group (ADR>16.608) compared to the low-ADR group (ADR≤16.608). Patients in the high-ADR group displayed elevated BMI and Na+ levels and reduced neutrophil count, monocyte count, globulin, and alkaline phosphatase (all p<0.05). Notably, the high-ADR group exhibited heightened DCR (96.7% vs. 89.2%, p=0.008) and ORR rates (70.1% vs. 51.0%, p=0.001) relative to the low-ADR group. Multivariate analysis outcomes indicated that high ADR constituted an independent risk factor for PFS (hazard ratio: 0.24, p<0.001). Furthermore, patients in the high-ADR cohort displayed a significantly prolonged median PFS (254 vs. 142 days, p<0.0001) compared to their low-ADR counterparts. In subpopulations exhibiting favorable implications for PFS, as determined by multivariate analysis, high-ADR patients consistently demonstrated extended PFS durations relative to the low-ADR group (all p<0.0001). Collectively, our findings suggest that ADR constitutes a novel and promising prognostic indicator for advanced LUAD patients, surpassing the accuracy of albumin and D-dimer individually and AFR. ADR thus serves as a potent instrument for assessing treatment effects and PFS in advanced LUAD patients undergoing first-line chemotherapy.

Inetetamab-based therapy in real-world treatment patterns with HER2-positive advanced breast cancer patients: a retrospective single-center study.

Inetetamab is a novel antibody targeting human epidermal growth factor receptor 2 (HER2) developed in China. Due to its optimized antibody-dependent cell-mediated cytotoxicity effect compared with trastuzumab, it has shown good efficacy and safety in the treatment of HER2-positive advanced breast cancer (ABC). This study aimed to investigate the efficacy and safety of inetetamab combination therapy in the treatment of HER2-positive ABC in real-world clinical practice. Retrospective study. A total of 133 patients with HER2-positive ABC who were treated with inetetamab-based regimens between March 2020 and January 2024 were retrospectively included in this study. The main endpoint was median progression-free survival (mPFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. The study included 133 HER2-positive ABC patients, and the median age was 55 years. The mPFS was 8.0 (6.7-9.3) months. The ORR was 50.4%, while the DCR was 88.7%. The mPFS for patients receiving inetetamab-based therapy as first to second, third to fourth, and later lines of metastatic treatment were 14.0, 7.0, and 6.0 months, respectively. Patients treated with inetetamab plus pyrotinib plus chemotherapy, especially with capecitabine, had the best outcomes (mPFS = 14.0 months). Multivariate analysis revealed that prior HER2-TKI treatment was significantly associated with worse PFS (hazard ratios 2.829, 95% confidence interval 1.265-6.328, p = 0.011). Subgroup analysis indicated that patients without visceral metastases had significantly better PFS (14.0 months vs 8.0 months, p = 0.003). The overall incidence of any grade adverse events (AEs) was 100%, with most being grades 1-2. Severe complications included neutropenia (37.6%) and leukopenia (33.1%). Inetetamab-based combination therapy shows promising efficacy and good safety in patients with HER2-positive ABC. It is one of the late-line treatment options for Chinese patients with HER2-positive ABC.

Dexamethasone and overall survival and progression free survival in patients with newly diagnosed glioblastoma: a meta-analysis.

Glioblastomas, the most common primary malignant brain tumors in adults, still hold poor prognosis. Corticosteroids, such as dexamethasone, are usually prescribed to reduce peritumoral edema and limit neurological symptoms, although potential detrimental effects of these drugs have been described. The present meta-analysis aimed to explore the association of dexamethasone with overall survival (OS) and progression free survival (PFS) in patients with newly diagnosed glioblastoma. PubMed, Cochrane Library, Embase, and ClinicalTrials.gov were searched for pertinent studies following the Preferred Reporting Items of Systematic Review and Meta-Analysis checklist. Pooled multivariable-adjusted hazard ratios (HR) for OS and PFS and their associated 95% confidence intervals (CIs) were calculated using the random-effects model and the heterogeneity among studies was assessed using I2. The quality of evidence was assessed using the GRADE criteria. Seven studies were included, pooling data of 1,257 patients, with age varying from 11 to 81 years. Glioblastoma patients on pre- or peri-operative dexamethasone were associated with a significantly poorer overall survival (HR: 1.33, 95% CI: 1.15, 1.55; 7 studies; I2: 59.9%) and progression free survival (HR: 1.77, 95% CI: 1.05, 2.97; 3 studies; I2: 71.1%) compared to patients not on dexamethasone. The quality of evidence was moderate for overall survival and low for progression free survival. Dexamethasone appeared to be associated with poor survival outcomes of glioblastoma patients.

Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial

ObjectiveIn the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors,...

First-line CDK4/6 inhibitor-based combinations for HR+/HER2- advanced breast cancer: A Bayesian network meta-analysis.

International guidelines recommend cyclin-dependent kinase 4/6 inhibitor (CDK4/6i)-based first-line therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, direct drug comparisons are lacking. We aimed to identify the most effective and safe therapy through network meta-analysis (NMA). We searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and OpenGrey up to September 30, 2023. Eligible studies included randomized controlled trials (RCTs) assessing endocrine therapy alone or in combination with CDK4/6i as first-line endocrine treatment for HR+/HER2- ABC patients. The hazard ratios for progression-free survival (PFS) and overall survival (OS) and relative risks for objective response rate and adverse events (AEs) were available in selected trials. We performed a Bayesian NMA following PRISMA guidelines. Thirteen RCTs, involving 10 treatments, were included. Most studies were at low risk of bias. Regarding PFS, ribociclib+fulvestrant ranked first with a surface under the cumulative ranking curve (SUCRA) of 85.0%, followed by dalpiciclib+nonsteroidal aromatase inhibitor (NSAI) (SUCRA=78.9%). Considering OS, the top three ranked treatments were ribociclib+fulvestrant (SUCRA=94.1%), abemaciclib+NSAI (SUCRA=69.9%), and ribociclib+NSAI (SUCRA=68.5%). Out of four CDK4/6is, ribociclib minimized the grade 3/4 AEs, while dalpiciclib demonstrated the worst safety. Publication bias could not be ignored in our analyses, and the certainty of evidence was downgraded primarily due to imprecision. Ribociclib+fulvestrant probably represents the best option in a first-line setting. When combined with NSAI, dalpiciclib likely showed the best efficacy but the worst safety. Abemaciclib+NSAI and ribociclib+NSAI could also be promising treatments, while palbociclib presented inferiority. (PROSPERO Registration No. CRD42022370271).

Antibiotic use reduces the efficacy of immune checkpoint inhibitors in patients with urothelial carcinoma: A systematic review and meta-analysis

ContextAntibiotics have been suggested to diminish the efficacy of immune checkpoint inhibitors (ICIs) by alterations of the gut microbiota. ObjectiveTo perform a meta-analysis summarizing the effect of antibiotics on the overall survival (OS) and progression-free survival (PFS) of urothelial cancer (UC) patients receiving ICI. Evidence acquisitionPubMed, EMBASE (Ovid), and the Cochrane Library were searched to identify studies published up to July 14, 2023. Studies reporting the associations between antibiotics use and OS and PFS in UC patients treated with ICI were included in this systematic review and meta-analysis. The random-effect model was used to pool the Hazard Ratios (HRs) for OS and PFS with 95% confidence interval (95%CI). The ROBINS-I was used to assess the risk of bias in the included studies, while the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework was used to inform the quality of evidence. Evidence synthesisThirteen nonrandomized studies involving a total of 5,095 ICI-treated UC patients were included in this review, of which 1434 (28%) received antibiotics. Overall, compared to patients who did not receive antibiotics, the pooled HRs for OS and PFS in those who received antibiotics were 1.45 [95% CI 1.25–1.68] and 1.40 [95% CI 1.05–1.87], respectively. Subgroup analysis revealed that the types of ICI and timing of antibiotic initiation did not influence the effect of antibiotics on OS and PFS in UC patients (P > 0.05). ConclusionsAntibiotic use significantly reduced OS and PFS in UC patients receiving ICI. While antibiotics remain crucial for the treatment of infections in UC patients, antibiotics should be prescribed cautiously in UC patients receiving ICI. Patient summaryAntibiotic use is associated with worsened survival in UC patients receiving immune checkpoint inhibitors.

Differential Effect of Consolidative Thoracic Radiation Therapy in Extensive-Stage Small Cell Lung Cancer Based on Sex

BackgroundThe landmark CREST trial demonstrated that consolidative thoracic radiotherapy (cTRT) improved overall (OS) and progression-free survival (PFS) after initial chemotherapy (chemo) in extensive-stage small cell lung cancer (ES-SCLC), with potentially increased benefit in women compared to men. It is unknown whether similar findings would apply after chemoimmunotherapy (chemo-IO) became the standard first-line treatment. In this analysis, we report national practice patterns and survival outcomes of cTRT according to patient sex. MethodsWe included patients from a nationwide de-identified electronic health record-derived database diagnosed with stage IV SCLC (2014-2021) who completed 4-6 cycles of first-line systemic therapy (platinum-doublet chemo or chemo-IO). We evaluated OS and PFS using multivariable Cox proportional hazards regression with receipt of cTRT as an independent variable and stratified by sex. As a sensitivity analysis, we weighted the models by the inverse probability of receiving cTRT. ResultsA total of 1,227 patients were included (850 chemo, 377 chemo-IO). There were no statistically significant differences in baseline characteristics between patients who did and did not receive cTRT. Among women, cTRT was associated with superior OS (adjusted hazard ratio (HR) 0.67; 95% confidence interval [CI] 0.52-0.87) and PFS (HR 0.63; 95% CI 0.49-0.82) compared to those not receiving cTRT. Conversely, no OS or PFS benefit with cTRT was observed in men [(OS HR 1.03; 95% CI 0.80-1.31; PFS HR 1.12; 95% CI 0.85-1.47)]. Findings were similar in weighted analyses. ConclusionThe survival efficacy of cTRT may be moderated by sex, with female patients appearing more likely to benefit than male patients. These findings reflect sex-based survival trends with similar effect sizes to those observed in the CREST trial. While the underpinnings of this association need to be elucidated, stratification by sex should be considered for RCTs studying cTRT in ES-SCLC.

Maintenance and consolidation strategies for patients with untreated advanced follicular lymphoma: A systematic review and network meta-analysis of randomized trials.

The emergence of novel and efficient antibody maintenance approaches has provided more options for post-induction treatment of advanced follicular lymphoma (FL), and further comparisons are required to determine the most clinically beneficial regimen. The authors conducted a systematic review and meta-analysis to evaluate the maintenance or consolidation strategy. The authors performed two independent searches in PubMed, Web of Science, the Cochrane library databases, Scopus, and Embase for randomized controlled trials (RCTs) evaluating maintenance or consolidation therapy in untreated FL patients. Extracted data included the clinical characteristics, treatment regimen, progression-free survival (PFS), overall survival (OS), and adverse effects. They then pooled the data and used a Bayesian random-effects model to combine direct comparisons with indirect evidence. The authors screened 1515 records and identified 13 eligible RCTs that assessed nine different regimens in 5681 advanced FL patients. Reconstructed individual survival data presented that obinutuzumab had the highest effect sizes and certainty of the evidence for PFS (hazard ratio, 0.43; 95% confidence interval, 0.22-0.79) and tolerability compared with observation. However, no benefit was observed in patients according to the OS, regardless of which regimen was taken. Considering other regimens, although an extended course of rituximab maintenance and consolidation therapies presented PFS benefits compared with standard rituximab maintenance, they were also associated with higher toxicity. Although obinutuzumab and rituximab maintenance treatment improved PFS significantly, its clinical benefit requires further validation in larger populations. Furthermore, because few trials informed each treatment comparison, research is needed to refine the understanding of this complex and rapidly evolving treatment landscape.

Bayesian survival extrapolation for cost-effectiveness analysis: a case study of RELAY for ramucirumab in combination with erlotinib in the treatment of non-small-cell lung cancer

Aim Increasing trend for progression-free survival (PFS)-based primary endpoint in oncology has led to lack of mature overall survival (OS) data at the time of approval. To address this evidence gap in economic evaluations, we used a joint Bayesian approach to predict survival outcomes using immature OS data from the RELAY trial. Methods Patient data from RELAY and systematic literature review (SLR) of phase 3 randomized clinical trials with hazard ratio (HR) estimates of mature PFS and immature OS were considered. OS and PFS were analyzed individually using a univariate model; bivariate analysis was performed using a joint model based on modified Bayesian normal induced copula estimation model. First, a Bayesian univariate model incorporated informative priors based on predicted HR and acceleration factor for OS and PFS. Second, a Bayesian-based joint model of RELAY PFS and OS data was based on the correlation between PFS and OS established in trials of similar populations. Marginal distribution of PFS was used to estimate the same for OS. Results Publications (N = 122) of first-line treatments in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer were identified in the SLR, of which 36 trials were linked to RELAY. Twenty-six trials with HR data were used. The univariate model could predict OS with reduced uncertainty compared with the frequentist approach. In the joint model, the marginal OS distribution borrowed strength from the marginal PFS distribution through the established correlation coefficient. Limitations Bayesian approach was successfully used in RELAY analysis but may not be universally applied to oncology trials due to the different associations of OS and PFS and different trial patient populations. Conclusions We demonstrated that both the univariate and joint Bayesian models reduced uncertainty in predicting OS compared to frequentist method. The methodology introduced here will have potential applications in clinical decision-making for other oncology trials.

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison.

Venetoclax is a standard treatment for patients with chronic lymphocytic leukemia (CLL) following covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi-pretreated CLL. Data from patients with CLL who were venetoclax-naïve and pretreated with cBTKi received pirtobrutinib (N=146) in the phase I/II BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (N=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events. Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% confidence interval [CI]: 0.58-1.73, P=0.98 and OS: 0.64, 95% CI: 0.25-1.67, P=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs. 64.8%, P=0.01). Grade ≥3 treatment-emergent adverse events were lower in weighted analyses for pirtobrutinib versus venetoclax (all P<0.01), except for pneumonia, which was similar. These results suggest that pirtobrutinib may also be considered as an effective and well-tolerated treatment for patients with relapsed CLL following cBTKi.

Telomere Length and DNA Methylation Epitype Both Provide Independent Prognostic Information in CLL Patients; Data from the UK CLL4, Arctic and Admire Clinical Trials

The presence of TP53 aberrations ( TP53ab) and/or unmutated IGHV genes (U-CLL) helps select initial treatment for CLL patients (Hallek 2018 &amp; Walewska 2022). However, many other biomarkers identified in recent years have failed to impact clinical decisions due to their coexistence with poor-risk indicators and uncertainty in their predictive abilities, often without suitable validation in long-term Phase II/III trials with comprehensive molecular analysis. We evaluated the clinical significance of two biomarkers, DNA methylation-based epitype (DME) and telomere length (TL), in (immuno-)chemotherapy clinical trials using samples from UKCLL4 (n=304) and ARCTIC/ADMIRE (ARC/ADM) (n=215). To our knowledge, DME and TL have not been assessed in a single study. Therefore, we utilized previously published DME (Wojdacz, 2019) and TL data (Strefford, 2015 &amp; Norris, 2019), supplemented with new MMQ-PCR data (n=60). TL cut-offs of short (TL-S, &amp;lt;2.92kb), intermediate (TL-I, 2.92-3.57kb), and long (TL-L, &amp;gt;3.57kb) and DME classifications of n-CLL (naive B-cell-like), i-CLL (intermediate B-cell-like) and m-CLL (memory B-cell-like) were employed. 73% of m-CLL and 50% of n-CLL patients harboured TL-L and TL-S, respectively (p&amp;lt;0.001, Figure 1). Additionally, n-CLL and TL-S were associated with poor-risk indicators, such as TP53ab and del(11q) (p&amp;lt;0.05, Figure 1). We then assessed the impact of 10 clinico-biological features, including DME, TL, age and treatment arm, on progression-free survival (PFS) and overall survival (OS) in CLL4 and ARC/ADM cohorts using univariate analysis (UA). The n-CLL group exhibited the shortest PFS and OS in the ARC/ADM cohort (PFS hazard ratio (HR):4.47, 95% confidence interval (CI):2.56-7.82 &amp; OS HR:3.95, CI:1.66-9.35, p&amp;lt;0.01), greater than the presence of TP53ab (PFS HR:4.39, CI:2.69-7.17 &amp; OS HR:3.77, CI:1.94-7.33, p&amp;lt;0.001). In CLL4, whilst TP53ab was the strongest predictor of PFS and OS (PFS HR:3.61, CI:2.39-5.44 &amp; OS HR: 3.66, CI:2.4-5.57, p&amp;lt;0.001), both n-CLL (PFS HR:1.96, CI:1.32-2.9 &amp; OS HR:2.8, CI:1.81-4.34, p&amp;lt;0.001) and TL-S (PFS HR:2.36, CI:1.7-3.29 &amp; OS HR:2.66, CI:1.87-3.76, p&amp;lt;0.001) were in the top five predictors of PFS and OS along with U-CLL and biallelic ATM inactivation ( biATM). Next, we performed Kaplan-Meier subgroup analysis, investigating DME in TL subgroups and vice versa. Examination of both biomarkers in the opposing subgroups in the ARC/ADM cohort, showed that TL could further stratify the i-CLL subgroup, with TL-L predicting longer PFS (median:6.12 years) compared to TL-S (HR:5.78, CI:2.34-14.33, median:3.8 years, p&amp;lt;0.001) or TL-I (HR:3.29, CI:1.4-7.76, median:4.35 years, p&amp;lt;0.01). As this pairwise analysis suggested that DME and TL may differentially contribute to outcome, we performed a multivariate cox regression, whilst controlling for confounding variables such as TP53ab and U-CLL. Covariates that were significant in UA were included in a stepwise backwards elimination process until a final model was reached. The CLL4 models were based on 246 subjects with 221 PFS and 205 OS events, ARC/ADM models were based on 138 and 176 subjects with 86 and 45 events for PFS and OS, respectively. For PFS models, TL-S emerged as significant (CLL4 HR:2.14, CI:1.39-3.3, p&amp;lt;0.001 &amp; ARC/ADM HR:2.18, CI:1.17-4.05, p&amp;lt;0.01) with a HR lower than TP53ab (CLL4 HR:3.38, CI:2.13-5.37 &amp; ARC/ADM HR:4.94, CI:2.58-9.48, p&amp;lt;0.001). DME emerged as significant for PFS in the CLL4 cohort (n-CLL HR:2.35, CI:1.37-4.05, p&amp;lt;0.01), along with SF3B1 mutation and treatment arm (Figure 2). In ARC/ADM, U-CLL, TP53ab, TL-S, del11q and biATM emerged as significant predictors of PFS (Figure 2). For OS, in both cohorts, TP53ab (CLL4 HR:2.77, CI:1.74-4.4, p&amp;lt;0.001 &amp; ARC/ADM HR:3.28, CI:1.64-6.55, p&amp;lt;0.001) and DME (CLL4 HR:2.07, CI:1.15-3.73, p&amp;lt;0.05 &amp; ARC/ADM, HR:3.4, CI:1.14-10.12, p&amp;lt;0.05) were found to predict shorter survival (Figure 2). Currently, we are integrating additional IGHV/IGLV data into our analysis, including the presence of IGLV3-21R110. In conclusion, by assessing the individual contribution of DME and TL to disease survival, we found that both variables offer valuable independent prognostic information when included in statistical models with poor-risk genomic lesions. TL and DME could help identify IGHV-mutated patients destined to respond poorly to (immuno-)chemotherapy, that might be more favourably treated with targeted agents.

Impact of Bevacizumab Being Skipped due to Adverse Events of Special Interest for Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab: An Exploratory Analysis of the Phase III IMbrave150 Study

Introduction: The phase III IMbrave150 study established atezolizumab + bevacizumab as the global standard of care in patients with unresectable hepatocellular carcinoma (HCC). This exploratory analysis examined the impact of bevacizumab interruption due to bevacizumab adverse events of special interest (AESIs). Methods: Patients in IMbrave150 who were randomized to atezolizumab + bevacizumab and received treatment for ≥6 months (to reduce immortal time bias) were included in group A-1 if bevacizumab had ever been skipped due to bevacizumab AESIs or to group A-2 otherwise. Efficacy analyses included overall survival (OS) and progression-free survival (PFS) by whether bevacizumab was skipped (group A-1 vs. A-2). PFS was evaluated per independent review facility (IRF)-assessed Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and HCC-modified RECIST (IRF-HCC mRECIST). Safety was also evaluated. Results: Of the 210 patients who received ≥6 months of atezolizumab + bevacizumab, 69 were assigned to group A-1 and 141 to A-2. At data cutoff (August 20, 2020), hazard ratio (HR) for OS was 1.04 (95% CI: 0.64, 1.69) for group A-1 versus A-2. HR for PFS was 1.07 (95% CI: 0.74, 1.55) per IRF-assessed RECIST 1.1 and 1.10 (95% CI: 0.76, 1.59; 15.5 vs. 9.7 months) per IRF-HCC mRECIST for group A-1 versus A-2. Safety profiles for atezolizumab and bevacizumab were largely similar between groups. More group A-1 patients had grade 3/4 adverse events. A separate analysis investigating the impact of immortal time bias in patients who received ≥3 months of atezolizumab + bevacizumab supported the appropriateness of the ≥6-month landmark analysis. Discussion/Conclusion: Efficacy was similar between patients who skipped bevacizumab due to bevacizumab AESIs and those who did not. Although this comparison was nonrandomized and exploratory, results suggest that skipping bevacizumab due to bevacizumab AESIs did not considerably impact the efficacy and safety of atezolizumab + bevacizumab.

Autologous Stem Cell Transplant in Fit Patients with Late Relapsed Diffuse Large B-Cell Lymphoma That Responded to Salvage Chemotherapy

Background: The new standard of care for fit patients with refractory or early relapse of diffuse large B-cell lymphoma (DLBCL) is chimeric antigen receptor T-cell (CAR-T) therapy. However, for patients with a relapse ≥12 months after completing frontline therapy, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT) remains the standard of care. There is a need to characterize such patients and their survival in view of the recent shift in treatment paradigm. Methods: Patients with DLBCL that relapsed ≥12 months after R-CHOP or R-CHOP-like frontline therapy who underwent salvage therapy and ASCT at Mayo Clinic or University of Iowa between 07/2000 and 4/2020 were identified from institutional lymphoma and transplant databases. Clinical characteristics, treatment information, and outcome data were abstracted. Progression-free survival (PFS) and overall survival (OS) from the time of ASCT were analyzed using Kaplan-Meier method and Cox proportional hazards models. Statistical analyses were performed in JMP v15. Results: A total of 158 patients with late relapsed DLBCL who underwent salvage chemotherapy and ASCT were identified. Baseline characteristics at relapse/ASCT are shown in Table 1. Median time from frontline therapy completion to 1st relapse was 26.4 months (range 12.0-152.4). Median age at relapse was 63 years (range 19-77), and 96 (61%) patients were male. A minority (3; 3%) had ECOG PS ≥2. 43 (52%) patients had an elevated serum LDH level, 70 (65%) had advanced stage disease, and 12 (11%) had &amp;gt;1 extranodal involvement. Median line of salvage therapy was 1 (range 1-3), and 17 (11%) patients required &amp;gt;1 line of salvage therapy. Best response before ASCT was complete response (CR) in 97 (61%) and partial response (PR) in 61 (39%). Median age at ASCT was 64 years (range 19-78). Median follow-up after ASCT was 91.5 months (95% CI 74.0-103.3). Median PFS and OS were 54.5 (95% CI 31.9-77.8) and 99.8 (95% CI 60.3-144.5) months, respectively. The 2-year PFS and OS rates were 64% (95% CI 56-71) and 81% (95% CI 74-87), respectively. No statistically significant difference in PFS was seen based on age at ASCT, sex, serum LDH, stage, or extranodal site involvement of &amp;gt;1 at relapse (Table 2). However, patients who required &amp;gt; 1 line of salvage therapy, compared to those requiring 1 line of salvage therapy, had significantly inferior PFS (median 6.1 vs 61.8 months, P &amp;lt;0.0001) and OS (17.8 vs 111.7 months, P &amp;lt;0.0004). There was no statistically significant difference in survival in patients who achieved CR vs PR prior to ASCT, with a median PFS of 61.8 vs 37.8 months( P=0.21) and a median OS of 111.7 vs 78.3 months ( P=0.62). Patients who achieved CR after 1 line of salvage therapy had the most favorable PFS and OS, with a median PFS of 65.6 vs 45.4 vs 6.1 vs 7.6 months ( P=0.0004) and a median OS of 133.0 vs 88.9 vs 24.2 vs 17.6 months ( P=0.004) in patients achieving CR after 1 line of salvage therapy vs PR after 1 line of salvage therapy vs CR after &amp;gt;1 line of salvage therapy vs PR after &amp;gt;1 line of salvage therapy, respectively (Table 2). In multivariate Cox regression models adjusted for age at ASCT and sex, patients requiring &amp;gt; 1 line of salvage therapy, compared to those who required 1 line of salvage therapy, had significantly inferior PFS with a hazard ratio (HR) of 3.25 (95% CI 1.82-5.78, P &amp;lt;0.0001) and OS with a HR of 3.50 (95% CI 1.86-6.60, P=0.0001). However, there remained no significant difference in survival based on response status (CR vs PR) with a HR for PFS 0.78 (95% CI 0.52-1.17, P=0.23) and OS 0.93 (95% CI 0.58-1.47, P=0.74). Conclusions: Survival after ASCT was excellent in patients with late relapsed DLBCL achieving CR after 1 line of salvage chemotherapy. Favorable survival outcomes were seen in patients who achieved PR after 1 line of salvage therapy. These data support the current clinical practice of ASCT consolidation in these patients. However, post-ASCT survival was poor in patients who required more than 1 line of salvage chemotherapy, despite achieving a satisfactory response to subsequent lines of salvage therapy. Alternative treatment strategies such as CAR-T therapy should be considered in such patients.

CD5 Expression in Mature T Cell Lymphoma

Background Mature T-cell lymphoma (TCL), an aggressive and heterogenous group of T cell neoplasms, constitutes less than 15% of adult non-Hodgkin lymphomas. CD5 is an inhibitory T cell receptor molecule expressed on mature T cells. CD5 expression has been associated with worse outcomes in B-cell malignancies, however this association has not been explored in TCL. Furthermore, CD5 has become a promising immunotherapeutic target for TCL. We herein aimed to characterize CD5 expression in TCL subtypes at diagnosis and relapse, and its association with clinical features and outcomes in a single center cohort. Methods We retrospectively identified 109 patients (pts) diagnosed with non-cutaneous and non-leukemic mature TCL, with data on CD5 expression on tumor tissue by immunohistochemistry (IHC) and/or flow cytometry (FC), from the electronic medical records at the Hospital of the University of Pennsylvania (HUP). CD5 positivity (CD5+) was defined as any percentage of CD5+ malignant cells on FC and/or IHC. Chi-square test was used to compare baseline pt characteristics at the initial presentation between CD5 expression groups. Treatment response (TR) was defined as achieving complete or partial response by the end of initial treatment. Logistic regression models were used to assess the impact of clinical parameters on the overall TR rate and odds ratios (OR) were computed. Cox proportional hazards models were used to evaluate the effects of clinical parameters on overall survival (OS) and progression-free survival (PFS) and were reported as hazard ratios (HR). We also conducted Kaplan-Meier (KM) analyses for OS and PFS by CD5 expression status. The OR and HR are reported with 95% CI in brackets. P-values &amp;lt;0.05 were considered significant. All analyses were conducted in SAS version 9.4 (SAS Institute Inc). Results We collected and evaluated data from a total of 109 adult pts diagnosed with TCL at HUP between 1/1/05-1/1/21. Median age at diagnosis was 58 (range: 19 - 86 years); 56% were men; the most common diagnosis was ALCL (n=37) followed by nodal TFH lymphoma (n=29), PTCL-NOS (n=16), ENKTCL (n=13) and other extranodal (EN) TCL (n=14) (Table.1). Compared to CD5- pts, a higher percentage of CD5+ pts were diagnosed at age &amp;gt;60 (CD5-:34.7%, CD5+:55.0%, p=0.0343), and stage 3 or 4 (CD5-:46.9%, CD5+:70%, p=0.0142), but fewer CD5+ pts had EN involvement at diagnosis (CD5-:77.6%, CD5+:50%, p=0.0031). CD5 was also differentially expressed by TCL subtypes: nearly all TFH TCL (93.1%) and PTCL-NOS expressed CD5 (87.5%), whereas CD5 was less commonly expressed in ALCL (39.4%,), other ENTCL (27.8%), and ENKTCL (7.7%) (p&amp;lt;0.0001). In addition, on univariate analysis (UVA), CD5 expression was associated with stage 3 or 4 (p=0.014), age &amp;gt;60 (p=0.034), and less common EN involvement (p=0.031), but not with treatment response, relapse or survival. On UVA for treatment response, established risk factors such as ≥ 2 EN involvement (OR=0.25 [0.09, 0.6], p=0.0243) and high LDH (OR=0.26 [0.08, 0.85], p=0.0267), were shown to be negative predictors. Multivariate analysis (MVA) for response also predicted high LDH as a negative predictor (OR=0.29 [0.08,0.99], p=0.0477). CD5 expression was not associated with treatment response on either UVA (OR=1.18 [0.50, 2.78], p=0.7042) or MVA (OR=1.00 [0.33,3.60], p=0.9969). On UVA, CD5 positivity did not impact OS (HR=1.2 [0.7,2.0], p=0.6118) nor PFS (HR=1.5 [0.7,3.0], p=0.2862), while worse outcomes were associated with established risk factors, including ECOG performance status ≥ 2 (OS HR=2.0 [1.0-3.8], p=0.0440), ≥2 EN involvement (OS HR=3.1 [1.7-5.7], p=0.0002; PFS HR 13.1 [2.9-59.9], p=0.0009), and B symptoms (OS HR=2.1 [1.2-3.7], p=0.0117). TFH TCL was also found to be associated with worse OS (HR= 2.6 [1.3-5.5], p=0.0101). In our cohort of 35 pts with CD5 expression data at relapses, 100% pts remained CD5+ (n=19), 68.75% pts remained CD5- (n=11), but 31.25% pts gained CD5 expression (n=5), and none lost CD5 expression. Based on KM analyses, CD5 expression did not impact PFS or OS (Fig. 1). Conclusions In this cohort of 109 TCL pts, CD5 expression was common in TFH TCL, PTCL-NOS, ALCL, and ENTCL, and was retained or gained at relapse, thus supporting its potential as a therapeutic target. CD5 expression was associated with advanced age and stage, while EN involvement was less common. CD5 expression was not associated with a differential treatment response, PFS, nor OS.

Chimeric Antigen Receptor (CAR) T Cell Infusion for Large B Cell Lymphoma in Complete Remission: A Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis

Introduction Axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) have been approved for the treatment of relapsed/refractory large B-cell lymphoma (LBCL). In some cases, patients are identified as being in radiographic complete remission (CR) after CAR T cell manufacturing. However, there are limited studies with small sample sizes that have reported outcomes for this specific group, and prospective data are lacking. We hypothesize that patients with LBCL who are in CR prior to CAR T cell infusion have favorable progression-free survival (PFS) and overall survival (OS) with lower toxicity. Methods We analyzed CIBMTR registry data from adult patients with LBCL who received commercial axi-cel, liso-cel, or tisa-cel infusion between 2018 and 2021 while in radiographic CR. Kaplan-Meier estimators were used to assess PFS and OS. The cumulative incidence of relapse, non-relapse mortality (NRM), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) was reported according to the consensus ASTCT criteria. Univariable hazard ratios (HR) for PFS and OS were analyzed using a Cox regression model to evaluate the prognostic impact of each variable. A forest plot was generated to display relevant factors. Results A total of 134 LBCL patients in CR prior to CAR T cell infusion were identified across 53 centers. The median follow-up was 24.3 months (range 0.9-49.4). Baseline demographics are presented in Table 1. After CAR T infusion, 7/134 patients (5.2%) proceeded to subsequent transplant (6 allogeneic, 1 autologous). At two years post-infusion, the probability of PFS and OS was 43.5% (95% CI 34.4-52.8) and 63.8% (95% CI 54.4-72.6), respectively. The cumulative incidence of NRM at two years was 9% (95% CI 4.5-15.4), and the incidence of relapse/progression was 47.3% (95% CI 38.2-56.6). The rate of grade 3 or higher CRS was 3/134 (2.2%), with median time to onset of 3 days (range 1-16). Grade 3 or higher ICANS occurred in 11/134 (8.2%) with a median time to onset of 6 days (range 2-15). On univariate analyses, PFS was worse in patients with 5 or more lines of prior therapy before CAR T cell infusion (HR 2.39, 95% CI 1.18-484) (see Figure 1). The most common cause of death was relapse or disease progression, accounting for 26/46 (56.5%) deaths, followed by infection (8/46, 17.4%, including 4 (8.7%) from COVID-19), ICANS (2 out of 46, 4.3%), and other causes. Conclusions CAR T cell infusion in patients with LBCL who are in CR after receiving two or more lines of prior therapy is feasible, with a subset of patients remaining free of progression at two years. The high NRM rate of 9% at two years highlights the importance of continued follow-up in this at-risk population. The CIBMTR is supported primarily by the Public Health Service U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); 75R60222C00011 from the Health Resources and Services Administration (HRSA); N00014-21-1-2954 and N00014-23-1-2057 from the Office of Naval Research.