Significant Improvement In Overall Survival Research Articles

Quantum-First Trial: FMS-like Tyrosine Kinase 3-Internal Tandem Duplication ( FLT3-ITD)-Specific Measurable Residual Disease (MRD) Clearance Assessed through Induction (IND) and Consolidation (CONS) Is Associated with Improved Overall Survival (OS) in Newly Diagnosed (nd) FLT3-ITD+ AML Patients (pts)

Background Detection of MRD by flow cytometry or gene fusion transcript quantitation increasingly is used to guide treatment decisions in AML. Molecular monitoring of recurrent gene mutations for MRD detection is an alternative strategy but, other than for nucleophosmin 1 ( NPM1) gene quantitation, remains controversial. FLT3-ITD is among the most common recurrent mutations in AML and confers a worse prognosis vs FLT3-wild-type and FLT3-TKD+ AML. Routine use of FLT3-ITD detection in remission as a predictor of relapse risk or OS has been limited by the low sensitivity of both conventional PCR-based detection methods and broad NGS platforms in clinical practice settings. More recently, FLT3-ITD-specific PCR-NGS assays such as getITD (PMID: 31089248) show greater sensitivity and ease of interpretation that point to eventual routine clinical application. However, the clinical value of these measurements has not been evaluated prospectively in large scale randomized controlled trials of FLT3 inhibitors. The phase 3 QuANTUM-First study (NCT02668653) evaluated the novel, potent, and highly selective type II FLT3 inhibitor quizartinib (Quiz) in nd FLT3-ITD+ AML pts and demonstrated that Quiz added to intensive IND and CONS, ± transplant, followed by single-agent continuation (CONT) therapy (Tx) resulted in a significant improvement in OS (PMID: 37116523). We analyzed if FLT3-ITD-specific MRD in QuANTUM-First pts impacted the clinical outcome or the benefits provided by Quiz in nd FLT3-ITD+ AML pts. Methods Genomic DNA, isolated from bone marrow aspirates or peripheral blood from pts after achievement of remission after 1 or 2 courses of IND and at end of CONS (prior to transplant or CONT cycle 1 day 1 [C1D1] for transplant pts and prior to CONT C1D1 for non-transplant pts), was analyzed with a FLT3-ITD PCR-NGS assay specifically developed for this trial (PMID: 31722002). ITD mutations detected after IND were cross-validated against the ITD detected at enrollment for each patient. Using a custom bioinformatics program, ITD mutations were identified, and variant allele frequencies (VAFs) were calculated with a sensitivity of 10 −5. MRD was classified as undetectable (using the 0 cutoff) or detectable above or below a 10 −4 predefined cutoff (based on lower limit of quantification for the assay). Comparisons of complete response (CR), composite complete response (CRc=CR+CRi), and the rate of pts achieving CRc during IND with no MRD between arms were made using a stratified Cochran-Mantel-Haenszel test. Comparison of FLT3-ITD VAF during IND and during CONS between arms was made using Wilcoxon rank sum test. All P-values were not adjusted for multiplicity. Results In QuANTUM-First, 539 nd FLT3-ITD+ AML pts were randomized to Quiz (n=268) or placebo (PBO; n=271). Of the 539 randomized pts, 368 (68.3%) achieved CRc after 1 or 2 courses of IND, and MRD analysis was performed on 321 (87.2%) of these pts (162 pts in Quiz and 159 pts in PBO) using samples collected at the time of response assessment during IND, before further Tx. MRD was also assessed in 337 pts (172 pts in Quiz and 165 pts in PBO) by end of up to 4 cycles of CONS prior to CONT/maintenance Tx. Of these pts, 166 additionally received transplant (87 in Quiz, 79 in PBO). The % of pts in CRc at end of IND with FLT3-ITD MRD of <10 −4 was similar between study arms (25.4% Quiz vs 21.8% PBO, nominal P = 0.3430), however, a greater % of pts in CRc had undetectable MRD with Quiz than PBO (12.3% vs 7.0%, nominal P = 0.0403). Among pts with CRc at end of IND, the median best FLT3-ITD VAF by end of CONS was lower (0% versus 0.0017%; nominal P = 0.0006) with Quiz vs PBO (Fig 1) and, using the 0 cutoff at end of IND, a longer OS was observed with Quiz vs PBO, regardless of MRD status, with a greater effect with Quiz (HR, 0.789 in MRD− pts; HR, 0.749 in MRD+ pts; Fig 2). In MRD+ pts, the median OS was not reached with Quiz and 35.4 months with PBO (Fig 2). Performing this analysis with an MRD cutoff of 10 ‒4 yielded similar findings (HR, 0.696 in MRD− pts; HR, 0.800 in MRD+ pts). Additional data about MRD impact on pts ± transplant in this trial will be presented. Conclusions These findings demonstrate the potential prognostic utility of FLT3-ITD-specific MRD measurements in the clinical management of pts with FLT3-ITD+ AML. Our data suggest that long-term OS benefits conferred by Quiz in part derive from a deep and sustained reduction of the FLT3-ITD+ leukemia burden.

Overall Survival of Warfarin Compared to LMWH/Doacs in Cancer-Associated Venous Thromboembolism: VA Cohort Study

Background: Warfarin has been shown in pre-clinical models to have anti-neoplastic activity. In a population-based study using the SEER-Medicare Linked Database warfarin was associated with improved survival compared to low molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs) in the treatment of cancer-associated thrombosis (CAT). To assess whether the observed survival advantage is consistent in other large cohorts, we performed a matched cohort study utilizing the Veterans Affairs (VA) database. The VA is a large, integrated health care system with comprehensive data for their patients at the individual level, which provides the optimal observational cohort to confirm the novel hypothesis warfarin confers a mortality benefit over LMWH. Method: Using the retrospective data from the VA health care system from 2000-2021, we identified patients with CAT who were > 18 years, had available prescription data for anticoagulation within 30 days of venous thromboembolism (VTE), and survived > 14 days after the index VTE event. Patients were excluded if they had prior diagnosis of VTE or had any anticoagulation prescription prior to the first coded VTE event. The primary outcome was overall survival (OS). Patients were matched 1:1 using nearest neighbor matching on the propensity score. The matching variables included cancer site, cancer stage, date of cancer diagnosis, date of VTE diagnosis, age at VTE diagnosis, gender, race, BMI, Elixhauser-based weighted comorbidity score, and rurality of residential status. Cox proportional-hazards regression was performed to estimate hazard ratios (HR) and 95% confidence intervals. Log-rank test was utilized to estimate the p-value. Subgroup analyses were performed in the largest groups of cancer available in the data set including prostate cancer, lung cancer, gastrointestinal cancer (excluding hepatobiliary cancer), and malignant hematologic neoplasms (including myeloid malignancy, lymphoid malignancy, and multiple myeloma). Finally subgroup analysis was also performed on localized cancer and metastatic disease based on AJCC stage grouping. Result: There were a total of 20,078 patients that met the inclusion and exclusion criteria without missing data. The warfarin cohort consistent of 8383 patients while non-warfarin cohort comprised 11696 patients. Among the non-warfarin cohort, 54% of the patients were prescribed LMWH exclusively and 38% of the patients were prescribed DOAC exclusively within 30days of the VTE diagnosis. The most common malignancies in the cohort included prostate (29.4%), lung (20.9%), gastrointestinal (15.7%) and hematologic malignancies (10.3%). Of patients with solid tumors, 22% had metastatic cancer. Among the VTE events, 33.3% were acute lower extremity deep vein thrombosis, 48.4% were acute pulmonary embolism, and 18.3% were acute upper extremity deep vein thrombosis. After propensity score matching, 8,383 patients were included in the warfarin arm and 8,383 patients in the non-warfarin arm. The median age at VTE diagnosis of the matched cohort was 69 [IQR 63 - 75] and the majority of the patients (96.7%) were male. Warfarin was associated with a significant improvement in OS compared to non-vitamin K antagonists (median OS, 1204 days [95% CI, 1137-1276 days] vs 703 days [95% CI, 665-747 days]; HR 0.79 [95% CI 0.76 - 0.82]; p-value <2x10 -16) (Figure1). The difference was also preserved in gastrointestinal malignancy (HR 0.8 v95% CI 0.73-0.87), lung cancer (HR 0.8, 95% CI 0.79-0.92) and prostate cancer (HR 0.71, 95% CI 0.65-0.77). The survival advantage was preserved in patients with metastatic (HR 0.86, 95% CI 0.78-0.83) and localized cancer (HR 0.80, 95% CI 0.76-0.84) (Figure 2). Conclusion and Relevance: In a population level propensity matched study, warfarin for the treatment of CAT was associated with significantly improved survival over non-vitamin K antagonist anticoagulation in CAT. These provocative finding confirm the previous observation in SEER-Medicare database and have important implications on patient care and health care costs. Further investigation into the biological basis of these findings could potentially lead to biomarker and drug discovery for cancer therapies and prognostication.

Recent Advancements in Acute Myeloid Leukemia Have Led to Incremental Improvement in Overall Survival

Background: Treatment approaches in acute myeloid leukemia are rapidly evolving due to a dynamic treatment landscape, routine molecular profiling, and the detection of measurable residual disease. Recently, there has been a surge in FDA approvals for novel therapies (e.g., midostaurin, gilteritinib, CPX-351, enasidenib, ivosidenib, and venetoclax), as well as a departure from a “one-size-fits-all” treatment approach. It is unclear, however, what effect these changes have had on overall survival over time. Since 2017, we have witnessed a significant introduction of novel therapeutics. We hypothesized that patients diagnosed after 2017 may have improved survival due to recent therapeutic advances. Methods: We retrospectively analyzed 627 consecutive patients in the Project ERIS database aged > 18 years with AML treated at VCU Massey Comprehensive Cancer Center from 2015 to 2022. We limited the analysis to January 1, 2015 to December 31, 2019 to avoid confounding from the COVID-19 pandemic. We obtained cytogenetic and molecular characteristics, induction regimens, allogeneic stem cell transplant status, and survival data. The median overall survival (mOS) was compared across calendar years using the Kaplan-Meier method. Categorical variables were analyzed using Fisher's exact test. Results: The median age at AML diagnosis was 62.9 years (range, 19.6-93.0), and the median ECOG performance status was 1 (range, 0-4). The median Charlson Comorbidity Index score was 5 (range, 0-14). There were 139 (22.2%) patients with ELN 2022 favorable-risk disease, 199 (31.7%) with intermediate risk, and 260 (41.5%) with adverse risk. The median OS of all patients diagnosed with AML in 2015 was 8.8 months. In 2016, the mOS was 14.5 months. There was a statistically significant improvement in mOS in 2016 compared to 2015 (HR 0.62 [95% CI 0.40-0.95], p = 0.027). The mOS in 2017, 2018, and 2019 was 12.9 months, 11.1 months, and 19.7 months, respectively. A significant improvement in OS was noted between 2015 and 2019 (HR 0.55 [95% CI 0.36-0.85], p = 0.003) in the entire cohort (Figure 1). When stratified by ELN 2022 genetic risk, clinically relevant improvement in OS was noted across all risk categories from 2015 to 2019, which reached statistical significance in the adverse risk group - favorable risk mOS: 16.4 months vs not reached (p = 0.141); intermediate risk: 13 months vs 18.7 months (p = 0.064); adverse risk: 7.2 months vs 13 months (p = 0.02). We observed expected changes in front-line treatment in this timeframe with decreased single-agent hypomethylating agent (HMA) usage in favor of HMA + venetoclax and increased intensive induction therapies outside of 7+3 (Figure 2). Strikingly, increased procession to allogeneic stem cell transplantation (HCT) was noted in the same timeframe (18.9% in 2015 vs 35.1% in 2019, p = 0.049). Conclusions : Our data demonstrate an emerging trend of clinically significant improvement in overall survival in patients with AML. The introduction of a multitude of therapeutic options may be associated with significantly improved survival over time. In addition to the advent of novel therapeutics leading to improved outcomes, the refinement of SCT conditioning regimens has likely led to the improved accessibility of HCT. In summary, we present an encouraging and significant trend of improved survival and access to HCT, particularly for patients with adverse-risk disease.

Combination of Decitabine and Etoposide Is Highly Effective in Treating p53-Mutated MDS/AML Via Activating Notch Signaling

The elderly MDS/AML patients, especially those with TP53 mutations, remain very difficult to treat and resistant to chemotherapy. A total of 105 elderly (age above 60 years) high risk MDS (n = 84, IPSS-R score > 4.5) or AML-MRC (n = 21) patients' records were collected from three medical centers across China and retrospectively analyzed. Decitabine and low dose etoposide was found to be superior to standard decitabine alone in MDS/AML patients with higher ORR (70.0% vs 52.7%) after two cycles of treatment, the longer median durations of ORR (24.0 months vs 12 months) and CR (38.0 months vs 24.0 months), and longer event-free survival (13 months vs 9 months, p = 0.023), without significant improvement in overall survival (20 months vs 15 months, p = 0.059). Other than the TP53 mutation, no other gene mutation (including NRAS, DNMT3A, TET2, EZH2, ASXL1, RUNX1) in the D+E group could reliably predict OS and EFS when compared to wild type phenotype. Patients with TP53 mutations showed higher response rate after two cycles of D+E therapy and had prolonged overall survival (Mutation vs WT: 31 months vs 9 months, p=0.012) and event-free survival (Mutation vs WT: 24 months vs 5 months, p = 0.022) compared with p53 wild type patients in D+E group from multivariate survival analyses. P53 mutated patients receiving D+E treatment also had significantly improved OS (31 months vs 12 months, p = 0.00) and EFS (24 months vs 8 months, p = 0.00) compared to patients receiving decitabine treatment. Moreover, we found decitabine and etoposide greatly reduced TP53 mutant AML tumor burden in the NSG mice xenografts (tumor burden: 92% reduction in p53-null xenograft mice, 65% reduction in p53-wild-type xenograft mice on day 20 after leukemia cells administration, p < 0.0001). It was found that TP53 mutant cells and p53 gene-editing MOLM13 cells showed terminal neutrophil differentiation in the combo of decitabine and etoposide, demonstrating the expected changes in cell-surface CD11b expression and neutrophil functional assays such as phagocytosis. Combo of decitabine and etoposide showed much higher percentage of differentiation marker expression compared to single drug decitabine or etoposide treatment. However, neither the p53 gene-edited THP-1 cells nor the TP53 wild type cell lines displayed markers of terminal differentiation, such as elevated CD11b expression or phagocytosis. Furthermore, the percentage of CD11b-positive cells increased significantly in p53-mutated primary cells while insignificantly in TP53 wild type cells. Decitabine and etoposide induced significant differentiation thus killing p53 mutated myeloid tumor cells and primary patients' cells in vitro. We also uncovered the underlying mechanism that why D+E could induce significant differentiation in TP53 Mutant while not in TP53 wild type myeloid tumors. Notch1 signaling pathway was activated after D+E treatment in TP53 Mutant myeloid tumors, which was consistently correlated with drug-induced myeloid differentiation. Notch1 knockout or Notch inhibitor incubation abrogated drug induced differentiation in TP53 Mutant myeloid tumors. The activation of the Notch1 signaling pathway has been observed to induce disease regression and decrease leukemia stem cells in AML mice as well as significant apoptosis in the AML patient sample. We also found D+E could upregulate transcription factor transcripts such as ETS1, ETS2, which could bind specifically to PSEN1 (PS1) promoter and activate its transcription directly. PS1 represent catalytic subunit of γ-secretase complexes and is responsible for Notch recognition. While in TP53 wild type AML cells, p53 might interact with p300. p300 acts as a coactivator of Ets1 and Ets2, competition for binding to p300 with p53 may confront p300 recruitment and repress ETS transcription activation directly, which might exert its effect on PS1 repression, thus inhibiting γ-secretase complex activity. In short, integrated p53 could repress PSEN1 transcription thus interfering gamma secretase complex activity, Notch recognition and cleavage as well as abrogating drug induced Notch activation and myeloid differentiation, which could be achieved in p53 mutated state. Combination of decitabine and etoposide regimen is also relatively safe and tolerable in elderly patients, which may open up a new path of therapy in the p53 mutated AML/MDS.

Improvements in Overall Survival in Older Patients with Mantle Cell Lymphoma Are Driven By Improvements across Multiple Lines of Therapy

Introduction Survival rates for people with mantle cell lymphoma (MCL) have improved in recent years. Among the potential factors accounting for this improvement is the approval of multiple new therapies over the past two decades, including bortezomib, bendamustine, ibrutinib, lenalidomide, acalabrutinib, and zanubrutinib. We hypothesized that the availability of multiple agents with non-overlapping mechanisms of action would result in significant improvements in overall survival following first-line therapy. Methods Patients diagnosed with MCL between 2002 and 2017 were identified using the SEER-Medicare linked database. Selected patients were >65 years of age at the time of diagnosis with MCL. Lines of therapy were determined using billing codes, with inpatient/outpatient claims used for traditional agents and Medicare Part D dataset used for oral agents. Next lines of therapy were defined based on claims for new anticancer agents separated from the end of the prior line by some certain number of days. Sensitivity analyses were performed varying the number of days between therapies. Overall survival (OS) was defined as initiation of initial therapy to death, while OS2 was defined as time from initiation of second-line therapy to death. Time to next therapy 1 (TTNT1) was defined as time from start of first-line therapy to death or start of second-line therapy, whichever came first. Cox models and Kaplan-Meier (KM) survival curves were generated for time-to-event analyses. Analyses were stratified by categories of years of first- and second-line therapies corresponding to eras of key drug approvals (e.g., 2002-2005, 2006-2009, 2010-2013, >2013). Results In total, 4,832 patients were included, among whom 3,840 patients (79.5%) had claims for first-line regimens and 1,648 (34.1% of total and 42.9% of patients with first-line regimens) had second-line regimens. Of the 4,832 patients, the majority were male (67.4%), White (94.6%), and non-Hispanic (94.7%), with good performance status (74.8%) and a Charlson Comorbidity Index <2 (64.8%). The median age at diagnosis was 75 (IQR 70-81). Patients with first- and/or second-line regimens did not differ significantly from the entire population of 4,832 patients with MCL in terms of baseline characteristics. In the first-line setting, use of bendamustine-rituximab (BR) increased from 2.3% of patients treated in 2006-2009 to 49.5% in 2014-2017. Similarly, use of single-agent BTK-inhibitors (BTKi) increased from nonexistent in patients treated in 2010-2013 to 13.8% in 2014-2017. In the second-line setting, use of single-agent BTKi similarly increased from 2.6% of those treated in 2010-2013 to 44.9% in 2014-2017. Median OS for the 3,840 patients with fist-line regimens was 4.4 years (95% CI, 4.1-4.5); median OS for those receiving first-line therapy in 2002-2005 was 3.5 years (3.1-3.9), compared to 3.7 (3.4-4.0), 4.5 (4.2-5.0), and not reached (4.8-NR) among those treated in 2006-2009, 2010-2013, and 2014-2017, respectively. Patients treated in 2014-2017 had significantly improved OS compared with those in 2002-2005 (log rank p<0.0001). Median TTNT1 overall was 2.5 years (2.4-2.6); median TTNT1 was 3.2 years (2.9-3.5) vs 2.3 years (2.1-2.6) for patients who received first-line therapy in 2014-2017 compared to 2002-2005 (log rank p<0.0001) ( Figure A). In addition, there was a significant difference across KM curves for OS2 stratified by categories of years of second-line therapy, with median OS2 of 2.5 (2.0-3.2) in patients treated in 2014-2017 compared to median OS2 of 2.1 (1.7-2.5) in 2010-2013 ( Figure B). Discussion In this analysis, we observed improvements survival of MCL patients over time, along with similar improvements in outcomes following first-line therapy, which may correlate with increased BR and BTKi use as first-line agents. Unexpectedly, improvements in survival following first-line therapy were considerably more modest. Potential explanations include lack of data from recent years during which we expect continued increased utilization of oral therapies vs unique impact of repeated therapies in the elderly. Overall, these data support the need for ongoing development of first- and subsequent-line therapies in MCL.

Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma

There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety. Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group. The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population. ClinicalTrials.gov Identifier: NCT03581786.

Patient-Reported Outcomes in Acute Myeloid Leukemia Patients with FLT3-ITD Mutation Receiving Quizartinib Vs. Standard Chemotherapy: Results from the Quantum-First Trial

Introduction: QuANTUM-First (NCT02668653) is a multicenter, global, randomized, double-blind phase 3 clinical trial evaluating the efficacy and safety of the novel oral fms-like tyrosine kinase 3 inhibitor (FLT3i) quizartinib in combination with standard induction and consolidation chemotherapy, and as maintenance monotherapy for up to 36 cycles in patients 18-75 years old with FLT3-ITD positive acute myeloid leukemia (AML). Quizartinib demonstrated a clinically meaningful and statistically significant improvement in overall survival (OS) versus placebo. An exploratory endpoint of the trial was to assess the impact of quizartinib on patient-reported outcomes (PROs). This is the first report of the longitudinal results of the PRO measures (PROMs) collected in the QuANTUM-First trial. Methods: Patients were randomized to receive chemotherapy + quizartinib or chemotherapy + placebo. PROMs were the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30) and EuroQol EQ-5D-5L. Baseline measurement was collected on day 8 of the first induction cycle, and repeated measurements were collected on day 28 of induction cycles 1-2, day 6 and 28 of consolidation cycles 1-4, and day 1 of continuation cycles 1-34 at 3-cycle intervals. EORTC QLQ-C30 and EQ-5D-5L scores were calculated as per their respective scoring manuals and included mean (95% CI, p-value) score for each domain of the EORTC QLQ-C30 and EQ-5D-5L index score, as well as mean change from baseline score at each timepoint. A minimal clinically important difference (MCID) score ≥10 points for each domain of the EORTC QLQ-C30, was considered clinically meaningful. A mixed-effect model for repeated measures (MMRM) and time until definitive deterioration (TUDD) was used to assess the longitudinal impact of treatment on PROs. TUDD was defined as time from baseline PRO score to first deterioration of the score beyond the MCID as compared to the baseline without further improvement of more than one MCID as compared to the reference score or without any further available score. Results: A total of 509 out of 539 patients from the trial (254 quizartinib; 255 placebo) were included for PRO analysis. Patient compliance to questionnaire completion at the beginning of each phase was high and similar for both arms and most scales (Global Health Status [GHS] completion rate (%) on induction cycle 1, consolidation cycle 1, and continuation cycle 1: 99.2, 95.3, 93.4, respectively) Baseline PRO scores were comparable between arms and were lower than the general population norm EORTC QLQ-C30 and EQ-5D-5L scores for EU and US (Table 1). Per MMRM, there were clinically meaningful improvements from baseline in GHS (Figure 1) and fatigue in both arms. However, there was no significant difference between arms for the change from baseline score although placebo arm had numerically better scores specifically during the maintenance phase (treatment difference for quizartinib - placebo was -2.0 [95% CI: -4.8, 0.7], p=0.1479 for GHS and 3.0 [95% CI: -0.1, 6.1], p=0.0600 for fatigue). Similar trends towards clinically meaningful improvement in score over time for both arms and no significant differences between arms were observed in most of the functional and symptom scales of EORTC QLQ-C30 and EQ-5D-5L index scores. By TUDD analysis, quizartinib arm showed slower deterioration in several scales (specifically GHS, cognitive function, appetite loss, and constipation) but the differences did not reach statistical significance. Conclusions: QuANTUM-First is the first study to explore the impact of quizartinib on PROs. Quizartinib showed improvement in OS without any detrimental impact on quality of life and symptoms when added to standard chemotherapy followed by maintenance monotherapy in patients with newly diagnosed FLT3-ITD AML.

A Meta-Analysis Comparing the Relative Efficacy of Pediatric-Inspired Regimens Versus Hyper-CVAD for the Treatment of Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma in Adolescents, Young Adults, and Adults

Background: Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL)are rare aggressive hematologic malignancies. Children with ALL/LBL have an overall favorable prognosis; however, adult patients (pts) have a poorer outcome. As a result, pediatric or pediatric-inspired regimens with asparaginase (ASP) have been used in adolescents and young adult (AYA) pts with ALL/LBL with promising results. Unfortunately, there are no prospective randomized studies comparing this approach with hyper-CVAD, a commonly used adult regimen not containing ASP. A meta-analysis was conducted to assess the efficacy of pediatric-inspired ASP-containing regimens compared with hyper-CVAD in treating ALL/LBL in AYA and adult pts. Methods: We performed a systematic literature review (using databases including PubMed, Embase, and Cochrane Library) to identify relevant studies comparing ASP-containing regimens and hyper-CVAD in pts with ALL/LBL published up to April 21, 2022. The search strategy consisted of title/abstract key words and subject headings describing key concepts of “acute lymphoblastic leukemia,” “lymphoblastic lymphoma,” “asparaginase,” “hyper-CVAD,” “refractory,” and “minimal residual disease.” Abstracts were screened for inclusion to identify full texts that were assessed for eligibility. To determine the effects of intervention on complete response (CR) and overall survival (OS) (2 commonly reported outcomes across identified studies), odds ratios (OR) and hazard ratios (HR) were calculated. A meta-analysis was conducted using both random- and fixed-effects models to estimate the pooled OR and HR, 95% confidence intervals (CIs), and 95% prediction intervals (PIs). Scenario analyses identified potential sources of heterogeneity and bias. Results: The initial search identified 46 primary publications of potential relevance: 12 studies directly compared ASP-containing regimens and hyper-CVAD, but none were randomized. Based on direct comparison studies, ASP-containing regimens had statistically significant improvement in median OS (4 studies), 2-year OS (1 study), 3-year OS (3 studies), and 5-year OS (1 study) compared with hyper-CVAD. Four studies with comparable demographics were suitable for meta-analysis (n=702 total pts; n=366 ASP-containing regimens; n=336 hyper-CVAD): 2 studies in AYA (aged 13-43 yrs) and 2 in adults of any age (aged >16 yrs). ASP-containing regimens in the included studies were all based on Berlin-Frankfurt-Münster (BFM) or Cancer and Leukemia Group B (CALGB)-10403 protocols. Pts treated with ASP-containing regimens had a significantly higher chance of achieving CR (random- and fixed-effects model: OR, 2.04 [95% CI: 1.31, 3.18]) and improved OS (random-effects model: HR, 1.76 [95% CI: 1.36, 2.29]; fixed-effects model: HR, 1.75 [95% CI: 1.36, 2.24]) than those treated with hyper-CVAD. There was a low level of heterogeneity among studies for both CR (I 2=0%, tau^2=0.00, P=0.86) and OS (I 2=0%, tau^2=0.02, P=0.79) data. One study evaluated 2 different ASP-containing regimens vs hyper-CVAD. Two separate meta-analyses were executed: 1 pooling results from both treatment arms (base case) and 1 considering them separately (scenario 1). A further analysis was limited to just 2 studies, where the proportionality assumption for the HR was robust and the results consequently most statistically reliable (scenario 2). Compared with the base case, both scenarios yielded similar estimates of treatment effect but with greater heterogeneity and wider PIs. This analysis has limitations: the type of ASP-containing regimen varied (1 study assessed L-ASP regimens, 2 assessed pegaspargase, and 1 did not specify), the studies each took place in different countries potentially contributing to heterogeneity in cultural, genetic, and healthcare practices, and not all details of pts' clinical characteristics were reported to inform on comparability of the pt populations. Further, without head-to-head studies, there was no way to address whether treatment cost or institutional bias affected the results. Conclusion(s): Meta-analysis suggests that ASP-containing regimens are associated with improved rates of CR and OS in AYA (median age range 13-43 yrs) and adult (median age range 16-60 yrs) pts.

Measurable Residual Disease As Assessed By Flow Cytometry As Predictor of Survival in Pediatric AML Patients

Introduction Pediatric acute myeloid leukemia (pedAML) is a heterogeneous group of hematological malignancies classified according to morphology, immunophenotyping, and genomics. The optimal adjustment of therapy based on level of response is not well defined. Aim: Herein, we present the results of a retrospective study aiming to analyze the prognostic value of measurable residual disease (MRD) as determined by flow cytometry (FC-MRD) in pediatric AML. Patients and Methods All pediatric and adolescent patients (aged 0-18 years old) with AML treated in our unit between 1/2013-6/2023 were included in this study. French American British (FAB) morphological classification, immune-phenotype analysis, and molecular characterization were performed on diagnosis, and all patients were treated according to AML-BFM protocols. Final risk classification was based on evaluation of response and on genetic abnormalities at diagnosis. MRD was assessed by FC-MRD after Induction 1 and 2, and, either after course 5 or before hematopoietic stem cell transplantation (HSCT). Complete Remission (CR) was defined as regenerative or normocellular bone marrow with <5% blasts; in peripheral blood ≥1.0x10 9/L neutrophil granulocytes and ≥80x10 9/L thrombocytes or Remission with partial regeneration ( CRp: regenerative or normocellular bone marrow with <5% blasts; in the blood: ≥1.0x10 9/L leukocytes, ≥0.5x10 9/L, neutrophil granulocytes and ≥50x10 9/L, self-sustained platelets), lasting at least 4weeks; no extramedullary disease. Overall survival (OS) was defined as the time interval from the treatment initiation date to the date of death due to any cause. Progressive free survival (PFS) was defined as the time interval from the response date to the date of disease relapse or death due to any cause. The probabilities of OS and PFS were estimated with the Kaplan-Meier method. Results Overall, there were 52 patients (median age at diagnosis:7 years, 37males/15 females) diagnosed with AML, of whom: 40 patients with de novo AML, 5 patients with therapy- or myelodysplasia-related AML and 7 patients with mixed-lineage leukemia. Cytogenetics were considered favorable for 16 (31.0%), intermediate for 4 (7.6%), and adverse for 32 (61.4%) patients. Standard-risk patients (n=16) received only chemotherapy, whereas all high-risk patients, and intermediate-risk patients with available matched donors, underwent HSCT should they have reached remission. Forty-four patients (84.6%) achieved complete response (CR). Among these patients, 43 patients (97.7%) achieved CR after 1 course of induction, and 1 patient (2.3%) required at least 2 courses. Twenty-four patients (46.1%) underwent HSCT during either their first (20/24) or second (4/24) CR. Overall, 12 patients (23.07%) died, 4 patients due to resistant disease, 3 patients due to relapse, 2 patients due to serious complications upon diagnosis, 1 patient due to infection and 2 patients due to transplant-related complications. With a median follow-up time of 3.7 years (range 0.1-11.1years), the five-year OS and PFS of the entire cohort was 74.0% and 70.0%, respectively. The level of FC-MRD was a significant prognostic factor for OS and PFS. More specifically, achievement of FC-MRD < 0.1% at all time points was associated with a significant improvement in PFS and OS. (figure 1). FC-MRD ≥ 0.1% after course 5 or before HSCT was the only independent adverse prognostic factor that was statistically significant for both progression-free (P=0.001) and overall survival (P<0.001) (figure1). Conclusions We investigated the association between FC-MRD and survival in Greek pediatric patients with AML. In our cohort, achieving an MRD status <0.1% according to FC is associated with significant improvement in the outcome of pediatric patients with AML.

Pomalidomide, Dexamethasone, and Daratumumab Versus Other Triplet Regimens in Patients with Relapsed or Refractory Multiple Myeloma: A Population-Adjusted Indirect Treatment Comparison

Introduction: Multiple myeloma (MM) is an incurable malignant plasma cell disorder in which most patients eventually relapse or become refractory to treatment. Lenalidomide (LEN) is typically administered as part of first-line regimens; however, patients who receive LEN usually relapse, necessitating improved options in later lines of therapy. The phase 2, non-randomized MM-014 trial (NCT01946477) demonstrated promising efficacy of pomalidomide (POM) plus dexamethasone and daratumumab (DPd) among patients with relapsed or refractory MM (RRMM), with an overall response rate of 77.7% and a median overall survival (OS) of 56.7 months at a median follow-up of 41.9 months. With the evolving treatment landscape of RRMM, however, there is limited head-to-head data comparing DPd to other standard of care therapies to inform clinical decision-making. Objective: To investigate the comparative efficacy of DPd versus non-POM-containing triplets in adult patients with RRMM using population-adjusted indirect comparison (PAIC) approaches. Methods: A PAIC was conducted using individual patient-level data of 112 adult patients with RRMM who were exposed to LEN (75.9% refractory to LEN) from cohort B of the MM-014 trial. Investigator-assessed OS was the primary endpoint of this analysis. A systematic literature review was performed to identify comparable interventional studies assessing the efficacy of non-POM-containing triplets for RRMM as well as potential prognostic variables (PVs). PVs verified by clinicians were selected for inclusion if significantly associated with OS (p < 0.1) in the MM-014 trial based on univariate Cox regression model. The suitability of these potential trials for PAIC was assessed by considering the comparability of study design, inclusion/exclusion criteria, patients' baseline characteristics, and outcomes. A retrospective analysis utilizing Flatiron electronic health record data from Jan 2011 to July 2022 was previously performed to evaluate the effect of LEN-refractory status on OS using multivariable Cox regression. Given the lack of a common comparator, unanchored PAIC was performed for OS using matching-adjusted indirect comparison (MAIC) and confirmatory simulated trial comparison (STC). A sensitivity analysis was conducted to explore the impact of LEN-refractory status as a PV. Results: Six trials were systematically identified as eligible comparators in initial screening including TOURMALINE-MM1, CANDOR, CASTOR, POLLUX, ASPIRE, and LEPUS. The analyses using Flatiron data showed that patients who were refractory to LEN had significantly shorter OS than those exposed to LEN but not refractory (Hazard ratio: 1.51; 95% CI: 1.17, 1.94), indicating the unsuitability to compare treatments based on studies with large variations in proportion of LEN-refractory patients. Four trials were excluded due to differences violating the transitivity assumption (0% LEN-refractory patients in TOURMALINE-MM1 and POLLUX; LEN-refractory status not reported in ASPIRE; only Chinese patients in LEPUS). The remaining two trials are phase 3 randomized controlled trials investigating carfilzomib plus dexamethasone and daratumumab (DKd) (CANDOR; NCT03158688; Usmani et al. Blood Adv. 2023; Epub ahead of print) and daratumumab plus bortezomib and dexamethasone (DVd) (CASTOR; NCT02136134; Sonneveld et al. J Clin Oncol. 2023; 41:1600-1609). In the base case MAIC adjusting for creatinine clearance, time from diagnosis, International Staging System score, and refractory to LEN, DPd was associated with numerical reduction in the risk of death compared to DKd and DVd (Table). In addition, the base case STC showed significant improvement of OS for DPd over DKd and DVd, confirming the findings from MAIC (Table). In the sensitivity analyses excluding LEN-refractory status, the effect estimates were substantially different from those in the base case analyses (>40% difference), demonstrating the importance of adjusting for LEN refractory status. Conclusions: In patients with RRMM, consistent OS benefit was found for DPd versus DKd and DVd regardless of the PAIC technique used. These findings support the use of DPd over DKd and DVd in treating patients with RRMM, especially given the oral route of administration of pomalidomide. This study also highlighted the importance of considering LEN refractory status when comparing efficacy of treatments for RRMM across trials.

Nivolumab plus chemotherapy in first-line metastatic non-small-cell lung cancer: results of the phase III CheckMate 227 Part 2 trial

In CheckMate 227 Part 1, first-line nivolumab plus ipilimumab prolonged overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% versus chemotherapy. We report results from CheckMate 227 Part 2, which evaluated nivolumab plus chemotherapy versus chemotherapy in patients with metastatic NSCLC regardless of tumor PD-L1 expression. Seven hundred and fifty-five patients with systemic therapy-naive, stage IV/recurrent NSCLC without EGFR mutations or ALK alterations were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus chemotherapy or chemotherapy. Primary endpoint was OS with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC. OS in all randomized patients was a hierarchically tested secondary endpoint. At 19.5 months' minimum follow-up, no significant improvement in OS was seen with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC [median OS 18.8 versus 15.6 months, hazard ratio (HR) 0.86, 95.62% confidence interval (CI) 0.69-1.08, P= 0.1859]. Descriptive analyses showed OS improvement with nivolumab plus chemotherapy versus chemotherapy in all randomized patients (median OS 18.3 versus 14.7 months, HR 0.81, 95.62% CI 0.67-0.97) and in an exploratory analysis in squamous NSCLC (median OS 18.3 versus 12.0 months, HR 0.69, 95% CI 0.50-0.97). A trend toward improved OS was seen with nivolumab plus chemotherapy versus chemotherapy, regardless of the tumor mutation status of STK11 or TP53, regardless of tumor mutational burden, and in patients with intermediate/poor Lung Immune Prognostic Index scores. Safety with nivolumab plus chemotherapy was consistent with previous reports of first-line settings. CheckMate 227 Part 2 did not meet the primary endpoint of OS with nivolumab plus chemotherapy versus chemotherapy in patients with metastatic nonsquamous NSCLC. Descriptive analyses showed prolonged OS with nivolumab plus chemotherapy in all-randomized and squamous NSCLC populations, suggesting that this combination may benefit patients with untreated metastatic NSCLC.

CTNI-56. FEASIBILITY AND EFFICACY OF AI-GUIDED PERSONALIZED PRECISION RADIATION THERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA: A MATCHED-CONTROL STUDY

Abstract PURPOSE The aim of this study was to evaluate the feasibility and efficacy of AI-guided personalized precision radiation therapy (PPRT) in improving outcomes for patients with newly diagnosed glioblastoma. METHODS In an open-label trial conducted at the University of Pennsylvania (NCT03477513), between August 2018 and April 2021, 17 patients with IDH-wildtype glioblastoma who underwent maximal safe resection were enrolled. They were matched with a cohort of glioblastoma patients based on age, sex, extent of resection (EOR), O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation status, and IDH status. Propensity Score Matching (PSM) was employed to assess the impact of the intervention on the likelihood of survival, using logistic regression to estimate the propensity score. Four patients were disqualified based on exclusion criteria. The PPRT group received personalized radiation dose escalation guided by AI-based predictive modeling of recurrence, along with concomitant and maintenance temozolomide chemotherapy. The control group received standard-of-care chemoradiotherapy between 2012 and 2020. In this study, we utilized a previously published and evaluated (retrospectively and prospectively) predictive AI model, which accurately estimated neoplastic cell infiltration and predicted future tumor recurrence using preoperative, multi-parametric MRIs. RESULTS Median overall survival was 24.4 months in the PPRT-temozolomide group and 17.9 months in the standard-of-care treatment group (hazard ratio, 0.34; 95% CI: 0.15-0.77; p = 0.009). PPRT was well-tolerated, with low-grade adverse events during radiation. Radiation necrosis occurred in 54% of the PPRT-temozolomide group and 36% of the standard-of-care group. CONCLUSION AI-guided PPRT in newly diagnosed glioblastoma patients demonstrated feasibility in routine clinical practice and led to a statistically significant improvement in overall survival compared to matched controls receiving standard-of-care treatment. These findings highlight the potential of personalized precision radiation therapy, with focused dose escalation, in enhancing outcomes for glioblastoma patients and emphasize the need for prospective validation in a randomized controlled clinical trial.

CTNI-54. A COMBINED ANALYSIS OF TWO RANDOMISED STUDIES EXPLORING THE IMPACT OF EXTENDED POST-RADIATION TEMOZOLOMIDE ON SURVIVAL OUTCOMES IN NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Stupp protocol uses 6 months, however, in routine care, it is often extended to 12 months, given its tolerability, lack of effective salvage treatments, and extended regimen in lower grade gliomas. METHODS GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled patients with newly diagnosed glioblastoma without progression at the end of 6 months post-radiation temozolomide. Participants were randomised in a 1:1 allocation to either six additional months (total 12 months) or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required for 80% power to detect an improvement in 6mPFS from 50% to 60%. Neither study recruited sufficient patients, so we performed a combined analysis of individual patient data. RESULTS 205 patients were recruited: 169 in GEINO14-01 (2014–2018) and 46 in EX-TEM (2019–2022). Median follow up was 20 and 14.5 months respectively. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR 0.75, p = 0.4), nor across any subgroups including MGMT methylated. There was no significant improvement in PFS (HR 0.92, P = 0.59, median 7.8 vs 9.7 months) or OS (HR 1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required changes to treatment, with 4.5% requiring dose delay, 7.5% dose reduction and 1.5% discontinuation of temozolomide. CONCLUSION For patients with newly diagnosed glioblastoma, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any individual patient subset that appeared to benefit from extended treatment. Six months should remain standard of care.

Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial

Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum-pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum-pemetrexed would improve overall survival in patients with pleural mesothelioma. We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m2] or carboplatin [area under the concentration-time curve 5-6 mg/mL per min] with pemetrexed 500 mg/m2, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual. Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66-75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3-27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4-21·3] with pembrolizumab vs 16·1 months [13·1-18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64-0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20-33%) with pembrolizumab and 17% (13-24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group. In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum-pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma. The Canadian Cancer Society and Merck & Co.

What health inequalities exist in access to, outcomes from and experience of treatment for lung cancer? A scoping review

ObjectivesLung cancer (LC) continues to be the leading cause of cancer-related deaths and while there have been significant improvements in overall survival, this gain is not equally distributed. To address...

Multidisciplinary Surgical Approach to Increase Survival for Advanced Ovarian Cancer in a Tertiary Gynaecological Oncology Centre.

The purpose of this paper is to report on changes in overall survival, progression-free survival, and complete cytoreduction rates in the 5-year period after the implementation of a multidisciplinary surgical team (MDT). Two cohorts were used. Cohort A was a retrospectively collated cohort from 2006 to 2015. Cohort B was a prospectively collated cohort of patients from January 2017 to September 2021. This study included 146 patients in cohort A (2006-2015) and 174 patients in cohort B (2017-2021) with FIGO stage III/IV ovarian cancer. Median follow-up in cohort A was 60 months and 48 months in cohort B. The rate of primary cytoreductive surgery increased from 38% (55/146) in cohort A to 46.5% (81/174) in cohort B. Complete macroscopic resection increased from 58.9% (86/146) in cohort A to 78.7% (137/174) in cohort B (p < 0.001). At 3 years, 75% (109/144) patients had disease progression in cohort A compared with 48.8% (85/174) in cohort B (log-rank, p < 0.001). Also at 3 years, 64.5% (93/144) of patients had died in cohort A compared with 24% (42/174) of cohort B (log-rank, p < 0.001). Cox multivariate analysis demonstrated that MDT input, residual disease, and age were independent predictors of overall (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.203-0.437, p < 0.001) and progression-free survival (HR 0.31, 95% CI 0.21-0.43, p < 0.001). Major morbidity remained stable throughout both study periods (2006-2021). Our data demonstrate that the implementation of multidisciplinary-team, intraoperative approach allowed for a change in surgical philosophy and has resulted in a significant improvement in overall survival, progression-free survival, and complete resection rates.

Comparing Efficacy of Erlotinib and Bevacizumab Combination with Erlotinib Monotherapy in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC): A Systematic Review and Meta-Analysis.

The objective of this systematic review and meta-analysis was to assess and contrast the efficacy and safety of combining erlotinib and bevacizumab with erlotinib alone in the treatment of patients with advanced non-small cell lung cancer (NSCLC). The authors searched databases such as PubMed, Medline, Scopus, and Cochrane Central Register of Controlled Trials for randomized control trials (RCTs) comparing erlotinib plus bevacizumab with erlotinib in NSCLC patients. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) were the outcomes of interest. The pooled hazard ratio (HR) and relative risk (RR) were estimated utilizing both fixed- and random-effect models. Methodological quality of the included studies was assessed using the Cochrane Risk of Bias tool. Nine studies comprising 1698 patients with NSCLC were included in this meta-analysis, of whom 850 were treated with erlotinib plus bevacizumab, and 848 with erlotinib. The erlotinib plus bevacizumab combination significantly prolonged PFS (HR, 0.62, 95% CI: 0.56, 0.70, p < 0.00001) but did not show any significant improvement in OS (HR, 0.95; 95% CI: 0.83, 1.07, p = 0.39) and ORR (HR, 1.10; 95% CI: 0.98, 1.24, p = 0.09). Increased risks of hypertension (RR, 5.15; 95% CI: 3.59, 7.39; p < 0.00001), proteinuria (RR, 10.54; 95% CI: 3.80, 29.20; p < 0.00001) and grade 3 and higher AEs (RR, 2.09; 95% CI: 1.47, 2.97; p < 0.00001) were observed with the erlotinib-plus-bevacizumab combination compared to erlotinib monotherapy. On subgroup analyses, the erlotinib plus bevacizumab combination improved PFS only. Combining erlotinib and bevacizumab has been shown to improve PFS in advanced NSCLC patients but did not show any significant OS and ORR benefits. Furthermore, risks of hypertension, proteinuria, and grade 3 or higher AEs were greater with the erlotinib-and-bevacizumab combination.

Current and Emerging Role of Monoclonal Antibody-Based First-Line Treatment in Advanced Gastro-Esophageal and Gastric Cancer.

Gastric cancer is the fifth most common malignancy worldwide and one of the main causes of cancer-related death. While surgical treatment is the only curative option for early disease, many have inoperable or advanced disease at diagnosis. Treatment in this case would be a combination of chemotherapy and immunotherapy. Gastro-esophageal (GEJ) and gastric cancer (GC) genetic profiling with current molecular diagnostic techniques has significantly changed the therapeutic landscape in advanced cancers. The identification of key players in GEJ and GC survival and proliferation, such as human epidermal growth factor 2 (HER2), vascular endothelial growth factor (VEGF), and programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1), has allowed for the individualization of advanced cancer treatment and significant improvement in overall survival and progression-free survival of patients. This review comprehensively examines the current and emerging role of monoclonal antibody-based first-line treatments in advanced GEJ and GC. We explore the impact of monoclonal antibodies targeting HER2, VEGF, PD-1/PD-L1, and Claudin 18.2 (CLDN18.2) on the first-line treatment landscape by talking about key clinical trials. This review emphasizes the importance of biomarker testing for optimal treatment selection and provides practical recommendations based on ASCO guidelines.

Autologous followed by allogeneic versus tandem-autologous transplantation in high-risk, newly diagnosed multiple myeloma: a systematic review and meta-analysis

ABSTRACTObjectives:High-risk multiple myeloma (HRMM) is associated with poor survival, despite many advances in antimyeloma strategies. Autologous followed by allogeneic stem cell transplantation (auto-allo-SCT) has yielded controversial results compared to tandem autologous stem cell transplantation (auto-SCT) in patients with HRMM. We conducted this meta-analysis to compare the efficacy and safety of auto-allo-SCT and tandem-auto-SCT in patients with HRMM.Methods:Embase, Cochrane Library, and PubMed databases were searched until March 2023. Prospective or retrospective studies comparing the effects of auto-allo-SCT and tandem-auto-SCT were included. Hazard ratios (HRs) and 95% confidence intervals (CIs) for time-to-event outcomes, and odds ratios (ORs) and 95%CIs for dichotomous outcomes were pooled using random-effects models.Results:Three studies involving 491 patients were included. Despite auto-allo-SCT seemed to be associated with improvements in progression-free survival (PFS) (HR [95%CI], 0.71 [0.51–1.00]) and complete response (CR) (OR [95%CI], 3.16 [1.67–5.99]), and reduced relapse/progression rates (47% vs. 55%) in comparison with tandem-auto-SCT, no marked improvement in overall survival (OS). In comparison to tandem-auto-SCT, patients assigned to auto-allo-SCT exhibited a higher risk of transplant-related mortality (TRM) (11.9% vs. 4.1%) and non-relapse mortality (NRM) (12.3% vs. 3.1%).Conclusion:Auto-allo-SCT seemed to be associated with improvements in PFS and CR when compared to tandem-auto-SCT in patients with HRMM, but it did not lead to a significant improvement in OS. Furthermore, patients in the auto-allo-SCT group were at a higher risk of developing TRM and NRM. Auto-allo-SCT transplantation should not be routinely incorporated into HRMM therapy but rather should be considered investigational.

The trade-off of post-mastectomy radiotherapy usage for the breast cancer patients aged 70 years or older: a study based on SEER database

BackgroundThis study aimed to investigate the role of post-mastectomy radiotherapy (PMRT) in the female aged 70 years or older diagnosed with breast cancer, which is still controversial.MethodsThis retrospective study enrolled female breast cancer women aged 70 + years following mastectomy from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was performed to reduce covariable imbalance. A nomogram was created to predict the 1,3,5-years overall survival (OS) and divide patients into three risk groups.ResultsAfter matching, PMRT were associated with significant improvement in breast cancer-specific survival (BCSS) and OS (p < 0.001). By contrast, the BCSS and OS benefit from PMRT were not significant in patients with T1N1 tumor (BCSS: HR = 0.716, p = 0.249;OS:HR = 0.908, p = 0.572), and T2N1 tumor (BCSS:HR = 0.866, p = 0.289;OS:HR = 0.879, p = 0.166). Stratified by subtype, the HR+/HER-2- subtype and the HR-/HER-2- subtype (all p < 0.001) have a significant prolonged survival, yet not significant BCSS difference are shown in the HER-2 + tumor. In the low-risk group as determined by the nomogram, the use of PMRT did not significantly improve OS (p = 0.203).ConclusionsThis study demonstrated that PMRT improves the survival of females with elderly breast cancer, while for T1-2N1 breast cancer patients, the omission of PMRT could be considered. Furthermore, the nomogram we constructed could be used as a decision tool for the omission of PMRT in low-risk elderly patients.