5-year PFS Research Articles

Preliminary results of a randomized controlled, open-label, multi-center phase II study of camrelizumab combined with chemotherapy followed by concurrent chemoradiotherapy and camrelizumab consolidation therapy versus standard chemoradiotherapy as first-line treatment for limited-disease small cell lung cancer.

e20132 Background: Immune checkpoint inhibitors combined with chemotherapy have significant clinical benefits in extensive-stage small cell lung cancer (SCLC). However, for patients with limited-disease SCLC (LD-SCLC), the data on immunotherapy combined with chemoradiotherapy is insufficient. Methods: In this open-label, multi-center, phase 2 trial, we randomly 1:1 assigned patients with previously untreated LD-SCLC to receive camrelizumab combined with chemotherapy followed by concurrent chemoradiotherapy (CCRT) and camrelizumab consolidation therapy or standard chemoradiotherapy. Patients with ECOG performance status of 0 to 1, and adequate organ function were eligible. For thoracic radiation, 45 Gy in 3 weeks (1.5 Gy, BID) was given on the first day of the third cycle of chemotherapy. An etoposide plus platinum-based regimen was given 4 cycles in total. Patients who had a good response to initial treatment were offered prophylactic cranial irradiation. The primary endpoint was the 1-year progression-free survival rate. We assumed that the 1-year PFS rate in the experimental group was expected to reach 65% compared to chemoradiotherapy alone group 45%, and planned to enroll 112 patients with 56 in each group. Results: Up to date, we have enrolled 40 patients. The median follow-up was 10.6 months. Safety was evaluated in all treated patients. No Grade 5 adverse event was observed. Grade 3 or 4 treatment-related adverse events occurred in 58.8% of the patients in the camrelizumab plus chemoradiotherapy and in 52.9% of those in the chemoradiotherapy alone group. The most frequent grade 3 or 4 adverse events were hematologic toxicities (70.6% vs. 58.8%). Acute esophagitis and pneumonitis of grade 3 occurred in both groups were 1/17 (5.9%) and 1/17 (5.9%), respectively. In the experimental group, only one patient was developed grade 3 immune pneumonia 1/17 (5.9%). The 1-year PFS rate was 54.5% (95% confidence interval [CI] 19.5%-89.6%) with camrelizumab plus chemoradiotherapy and 44.4% (95% CI 3.9%-88.0%) with chemoradiotherapy alone. Among the 17 patients who received camrelizumab, the median PFS time was not reached, as compared with 14.35 (95% CI, 8.15-20.91) months among the 17 patients with chemoradiotherapy alone. Conclusions: In patients with LD-SCLC, the addition of camrelizumab to chemoradiotherapy did not increase the incidence of adverse events. Camrelizumab plus chemoradiotherapy resulted in an encouraging 1-year PFS rate. Larger sample sizes and longer follow-up times are required to validate our preliminary results. Clinical trial information: ChiCTR2000032275.

Use of liquid biomarker thymidine kinase activity (TKa) to predict outcome and progression in patients with metastatic breast cancer (MBC) in the GEICAM/2014-12 FLIPPER trial.

1028 Background: There is a need for more precise blood-based tumor biomarkers in MBC. TKa is a liquid proliferation biomarker providing prognostic, predictive and monitoring information in MBC. TKa can be measured in blood using the DiviTum TKa assay. Here we report the results of TKa in a trial of endocrine therapy (ET) fulvestrant (F) + the CDK4/6 inhibitor (CDK4/6i) Palbociclib (Pa) vs. F + Placebo (Pl), the GEICAM FLIPPER trial (NCT02690480), a multicenter, double-blind, randomized (1:1) study. F+Pa showed 1-year PFS rates of 83.5% vs. 71.9% (p=0.064) and better median (m)PFS (31.8 vs. 22.0 months, p=0.001) than F+Pl in first line treatment of HR+/HER2- MBC patients. F+Pa also significantly improved ORR and CBR. ET+CDK4/6i are currently the cornerstone of treatment for HR+/HER2- MBC. However, 10-30% of these patients display primary resistance to treatment. Early identification of patient subsets with different risk of progression during treatment with CDK4/6i may help tailor clinical management and disease monitoring. Methods: Sequential plasma was collected from 187 patients (pts) at baseline (BL) and at 12, 24, 36, 48 weeks (w) on treatment, and at progression. 910 samples were analyzed for TKa with the FDA approved and CE labelled DiviTum TKa assay (Biovica, Sweden) using DuA (DiviTum unit of Activity) as measuring unit. The cutoff for categorizing in high vs low is 250 DuA. The Kaplan-Meier method was used to estimate mPFS and mOS. Unadjusted and adjusted hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were calculated with the Cox proportional hazards regression model and with logistic regression respectively, considering relevant confounders. Results: Low BL TKa predicted better PFS (30.5 months mPFS in low vs 19.8 in high, HR 1.62; 95% CI 1.11-2.35, p=0.011) and OS (HR 1.81; 95% CI 1.15-2.85, p=0.0099). Higher TKa at BL and at 12w was detected in pts that progressed before 12 months. Conversely, low BL TKa, maintained throughout week 12-48, were associated with objective response (HR 2.58; 95% CI 1.38-4.81, p=0.0029) and OS (HR 5.74; 95%CI 2.06-16, p=0.0008). At progression, pts on F+Pa tended to have higher TKa levels than F+Pl (246 vs. 138 DuA), reflecting faster growing tumors, not achieving statistical significance (p=0.0585). TKa monitoring and dynamics from BL and on treatment timepoints (week 12-48) show that the group of pts with low TK at BL that remain low during treatment is enriched with non-progressors and pts that progress after 12 months (p=0.0108). High TKa at BL predicted shorter OS in the F+Pa arm (HR 4.39; 95% CI 2.15-8.99, p<0.0001). Conclusions: Measuring blood TKa levels can monitor and predict efficacy of F+/-Pa at BL and during therapy in MBC. TKa dynamics before and during therapy are associated with PFS and OS. Future studies will provide additional knowledge on the utility of TKa in MBC. Clinical trial information: NCT02690480 .

F.3 Multicentre prospective validation of integrated molecular classification of meningiomas and prediction of recurrence risk using DNA methylation

Background: Meningiomas have significant heterogeneity between patients, making prognostication challenging. For this study, we prospectively validate the prognostic capabilities of a DNA methylation-based predictor and multiomic molecular groups (MG) of meningiomas. Methods: DNA methylation profiles were generated using the Illumina EPICarray. MG were assigned as previously published. Performance of our methylation-based predictor and MG were compared with WHO grade using generalized boosted regression modeling by generating time-dependent receiver operating characteristic (ROC) curves and computing area under the ROC curves (AUCs) along with their 95% confidence interval using bootstrap resampling. Results: 295 meningiomas treated from 2018-2021 were included. Methylation-defined high-risk meningiomas had significantly poorer PFS and OS compared to low-risk cases (p<0.0001). Methylation risk increased with higher WHO grade and MG. Higher methylome risk (HR 4.89, 95%CI 2.02-11.82) and proliferative MG (HR 4.11, 95%CI 1.29-13.06) were associated with significantly worse PFS independent of WHO grade, extent of resection, and adjuvant RT. Both methylome-risk and MG classification predicted 3- and 5-year PFS and OS more accurately than WHO grade alone (ΔAUC=0.10-0.23). 42 cases were prescribed adjuvant RT prospectively although RT did not significantly improve PFS in high-risk cases (p=0.41). Conclusions: Molecular profiling outperforms conventional WHO grading for prognostication in an independent, prospectively collected cohort of meningiomas.

Estimating the long-term survival of unresectable stage III non-small cell lung cancer based on cure model analysis

BackgroundThe predictors of long-term survival and appropriate surrogate endpoints in unresectable stage III non-small cell lung cancer (NSCLC) treated with radiotherapy remain unclear, especially in the immune therapy era. MethodsThis study retrospectively analyzed a prospective cohort of 822 patients treated at the Chinese National Cancer Center from 2013 to 2022. Cure fractions, surrogates for long-term survival, and associated factors were assessed using a mixture cure model, with validation against a matched Surveillance, Epidemiology, and End Results (SEER) dataset. Results27.3% of patients with unresectable stage III NSCLC can achieve long-term survival after treated by radiotherapy. 4-year PFS and 5-year OS, when 80% of patients were considered cured, showed significant correlations with cure rates based on background mortality-adjusted PFS and relative survival, with R-squared values exceeding 0.85. Independent predictors of long-term survival included non-squamous cell carcinoma (non-SCC) pathological type, N category, gross tumor volume, and treatment combination with immune checkpoint inhibitors (ICIs). ConclusionsRadiotherapy, especially when combined with ICIs, offers a potential cure for a proportion of patients with unresectable stage III NSCLC. Tumor burden and ICIs are key predictors of long-term survival. The study suggested 4-year PFS and 5-year OS as surrogate endpoints for cure and long-term survival assessment.

The safety and efficacy of bevacizumab in treatment of recurrent low-grade glioma: a systematic review and meta-analysis.

Central nervous system (CNS) tumors are among the most common malignancies in various age ranges. Low-grade glioma (LGG) can account for nearly 30% of pediatric CNS malignancies. Progression or recurrence after the first-line treatments is common among these patients. Therefore, more treatments are required. Bevacizumab as an anti-VEGF antibody has come into the spotlight recently and is especially used in relapse or recurrence settings. This review aims to study the safety and efficacy of bevacizumab for patients with recurrent LGG. This study was conducted according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PubMed, Scopus, Web of Science, and Embase were comprehensively searched using the relevant key terms until 24th August 2023 to retrieve the studies that investigated clinical outcomes of bevacizumab in patients with recurrent LGG. All statistical analysis was performed by STATA v.17. A total of 1306 papers were gathered, out of which 13 were incorporated in the meta-analysis. The pooled incidence rate of treatment according to the RANO scale was 70% (95% CI = 43-98%) for objective response rate, 26% (95% CI = 58-96%) for partial response, 21% (95% CI = 15-28%) for minor response, 14% (95% CI = 3-24%) for complete response, 48% (95% CI = 37-59%) for stable disease, and 8% (95% CI = 4-11%) for progressive disease. Furthermore, according to progressive survival after treatment, it was 4% (95% CI = -1 to 9%) for 6-month PFS, 41% (95% CI = 32-50%) for 2-year PFS, and 29% (95% CI = 22-35%) for 3-year PFS. According to the RANO scale and PFS, clinicians should be aware that Bevacizumab could be a favorable alternative therapy for recurrent LGG. Furthermore, bevacizumab exhibits minimal toxicity and high tolerability in recurrent LGG.

Outcomes of patients in nasopharyngeal adenoid cystic carcinoma in the IMRT era: a single-center experience

ObjectiveNasopharyngeal adenoid cystic carcinoma (NACC) is a rare malignancy with special biological features. Controversies exist regarding the treatment approach and prognostic factors in the IMRT era. This study aimed to evaluate the long-term outcomes and management approaches in NACC.MethodsFifty patients with NACC at our institution between 2010 and 2020 were reviewed. Sixteen patients received primary radiotherapy (RT), and 34 patients underwent primary surgery.ResultsBetween January 2010 and October 2020, a total of 50 patients with pathologically proven NACC were included in our analysis. The median follow-up time was 58.5 months (range: 6.0–151.0 months). The 5-year overall survival rate (OS) and progression-free survival rate (PFS) were 83.9% and 67.5%, respectively. The 5-year OS rates of patients whose primary treatment was surgery and RT were 90.0% and 67.3%, respectively (log-rank P = 0.028). The 5-year PFS rates of patients whose primary treatment was surgery or RT were 80.8% and 40.7%, respectively (log-rank P = 0.024). Multivariate analyses showed that nerve invasion and the pattern of primary treatment were independent factors associated with PFS.ConclusionsDue to the relative insensitivity to radiation, primary surgery seemed to provide a better chance of disease control and improved survival in NACC. Meanwhile, postoperative radiotherapy should be performed for advanced stage or residual tumours. Cranial nerve invasion and treatment pattern might be important factors affecting the prognosis of patients with NACC.

REPeated mAgnetic resonance Image-guided stereotactic body Radiotherapy (MRIg-reSBRT) for oligometastatic patients: REPAIR, a mono-institutional retrospective study

BackgroundOligo-progression or further recurrence is an open issue in the multi-integrated management of oligometastatic disease (OMD). Re-irradiation with stereotactic body radiotherapy (re-SBRT) technique could represent a valuable treatment option to improve OMD clinical outcomes. MRI-guided allows real-time visualization of the target volumes and online adaptive radiotherapy (oART). The aim of this retrospective study is to evaluate the efficacy and toxicity profile of MRI-guided repeated SBRT (MRIg-reSBRT) in the OMD setting and propose a re-SBRT classification.MethodsWe retrospectively analyzed patients (pts) with recurrent liver metastases or abdominal metastatic lesions between 1 and 5 centimeters from liver candidate to MRIg-reSBRT showing geometric overlap between the different SBRT courses and assessing whether they were in field (type 1) or not (type 2).ResultsEighteen pts completed MRIg-reSBRT course for 25 metastatic hepatic/perihepatic lesions from July 2019 to January 2020. A total of 20 SBRT courses: 15 Type 1 re-SBRT (75%) and 5 Type 2 re-SBRT (25%) was delivered. Mean interval between the first SBRT and MRIg-reSBRT was 8,6 months. Mean prescribed dose for the first treatment was 43 Gy (range 24–50 Gy, mean BEDα/β10=93), while 41 Gy (range 16–50 Gy, mean BEDα/β10=92) for MRIg-reSBRT. Average liver dose was 3,9 Gy (range 1–10 Gy) and 3,7 Gy (range 1,6–8 Gy) for the first SBRT and MRIg-reSBRT, respectively. No acute or late toxicities were reported at a median follow-up of 10,7 months. The 1-year OS and PFS was 73,08% and 50%, respectively. Overall Clinical Benefit was 54%.ConclusionsMRIg-reSBRT could be considered an effective and safe option in the multi-integrated treatment of OMD.

Predictors of Survival, Treatment Modalities, and Clinical Outcomes of Diffuse Large B-Cell Lymphoma in Patients Older Than 70 Years Still an Unmet Medical Need in 2024 Based on Real-World Evidence.

Diffuse large B-cell lymphoma (DLBCL) especially affects the older population. Old (≥60 years) and very old age (≥80 years) DLBCL patients often present high-risk molecular alterations, lower tolerability to conventional immunochemotherapy, and poor clinical outcomes. In this scenario, attenuated therapeutic strategies, such as the R-MiniCHOP and R-MiniCHOP of the elderly regimens, have emerged for this particularly fragile population. However, the responses, clinical outcomes, and toxicities of these regimens currently remain poorly understood, mainly because these individuals are not usually included in controlled clinical trials. This retrospective, observational, and single-center real-world study included 185 DLBCL, NOS patients older than 70 years treated at the largest oncology center in Latin America from 2009 to 2020. We aimed to assess the outcomes, determine survival predictors, and compare responses and toxicities between three different primary therapeutic strategies, including the conventional R-CHOP regimen and the attenuated R-MiniCHOP and R-MiniCHOP of the elderly protocols. The median age at diagnosis was 75 years (70-97 years), and 58.9% were female. Comorbidities were prevalent, including 19.5% with immobility, 28.1% with malnutrition, and 24.8% with polypharmacy. Advanced clinical stage was observed in 72.4%, 48.6% had bulky disease ≥7 cm, 63.2% had B-symptoms, and 67.0% presented intermediate-high/high-risk IPI. With a median follow-up of 6.3 years, the estimated 5-year OS and PFS were 50.2% and 44.6%, respectively. The R-MiniCHOP of the elderly regimen had a lower ORR (p = 0.040); however, patients in this group had higher rates of unfavorable clinical and laboratory findings, including hypoalbuminemia (p = 0.001), IPI ≥ 3 (p = 0.013), and NCCN-IPI ≥ 3 (p = 0.002). Although associated with higher rates of severe neutropenia (p = 0.003), the R-CHOP regimen promoted increased OS (p = 0.003) and PFS (p = 0.005) in comparison to the attenuated protocols. Additionally, age ≥ 75 years, high levels of LDH, B-symptoms, advanced clinical stage (III/IV), neutrophilia, and low lymphocyte/monocyte ratio were identified as poor prognostic factors in this cohort. In this large and real-life Latin American cohort, we demonstrated that patients with DLBCL, NOS older than 70 years still do not have satisfactory clinical outcomes in 2024, with half of cases not reaching 5 years of life expectancy after diagnosis. Although the conventional R-CHOP offers response and survival advantages over attenuated regimens, its myelotoxicity is not negligible. Therefore, the outcomes reported and the prognostic factors here identified may assist clinicians in the appropriate selection of therapeutic strategies adapted to the risk for old and very old DLBCL patients.

Patterns of Treatment Failure in Primary Central Nervous System Lymphoma.

Progression of PCNSL remains a challenge with salvage therapies, including the risk of substantial morbidity and mortality. We report patterns of first tumor progression to inform opportunities for improvement. This is an institutional retrospective review from 2002 to 2021 of 95 consecutive patients with pathologically confirmed PCNSL, of whom 29 experienced progressive disease. Kaplan-Meier method, log-rank test, and Cox proportional hazard models are used to characterize associations of patient, tumor, and treatment variables with LC, PFS, and patterns of first failure. Most patients were below 65 years old (62%) with KPS >70 (64%) and negative CSF cytology (70%). In 70 patients with MRIs, the median tumor volume was 12.6 mL (range: 0.5 to 67.8 mL). After a median follow-up of 11 months, 1-year PFS was 48% and 1-year LC was 80%. Of the 29 patients with progression, 24% were distant only, 17% were distant and local, and 59% were local only. On MVA, LC was associated with age (HR: 1.08/y, P =0.02), KPS (HR: 0.10, P =0.02), completion of >6 cycles of HD-MTX (HR: 0.10, P <0.01), and use of intrathecal chemotherapy (HR: 0.03, P <0.01). On UVA, local only first failure trended to be increased with >14 mL tumors (OR: 5.06, P =0.08) with 1-year LC 83% (<14 mL) versus 64% (>14mL). There were no significant associations with LC and WBRT ( P =0.37), Rituximab ( P =0.12), or attempted gross total resection ( P =0.72). Our findings reaffirm the importance of systemic and intrathecal therapies for local control in PCNSL. However, bulky tumors trend to fail locally, warranting further investigation about the role of local therapies or systemic therapy intensification.

Abstract CT037: A phase I investigator-initiated trial of evorpacept (ALX148), lenalidomide and rituximab for patients with relapsed or refractory B-cell non-Hodgkin lymphoma

Abstract Introduction. We have recently demonstrated that pro-tumoral SIRPα+ macrophages may mediate resistance to lenalidomide and rituximab (R2) in patients (pts) with relapsed or refractory (RR) B-cell non-Hodgkin lymphoma (B-NHL). Evorpacept (ALX148) is a novel high-affinity CD47 blocker that abrogates the ‘do-not-eat-me signal’ provided to SIRPα+ macrophages. In a phase I trial including 33 pts with RR B-NHL it was well tolerated in combination with rituximab. We hypothesized that evorpacept and R2 will be synergistic, and the combination will be safe and effective for the treatment of pts with RR B-NHL. Methods. This single arm phase I study (NCT05025800) was conducted between 11/2021 and 9/2023 (data cut-off 12/2023). Adult pts with RR B-NHL who had received at least 2 prior lines of systemic therapy (1 in case of indolent B-NHL [iNHL]) were included. Evorpacept was administered intravenously (IV), in a 28-day cycle, for 12 cycles, at two dose levels (DL): 30 mg/Kg on day (D) 1 and D15 (DL1), or 60 mg/Kg on day 1 (DL2); rituximab IV was given weekly during cycle 1, and on D1 during cycles 2-6; lenalidomide was given orally on D1-21 during cycles 1-6. Dose limiting toxicity (DLT) was evaluated according to CTCAE v5 during cycle 1 and a Bayesian Optimal Interval design was used, with a target DLT rate of 0.3. Response was assessed according to Lugano 2014 criteria. Results. Twenty pts were included in the study. Median age was 61 (27-85), 10 (50%) were male, and 7 (35%) were non-white; 15 (75%) had follicular lymphoma, 3 (15%) marginal zone lymphoma, 1 (5%) mantle cell lymphoma, and 1 (5%) Richter Syndrome; 20 (100%) had previously received an anti-CD20 monoclonal antibody, 13 (72%) chemoimmunotherapy, and 15/18 (83%) iNHL pts had intermediate-high FLIPI. Three pts were treated at DL1, 17 at DL2, and no DLT was observed. The most common grade 3-4 adverse events included: neutropenia (55%), infections (30%), ALT increase (15%), AST increase (10%), skin rash (10%), and anemia (10%). Eight (40%) pts experienced a cycle delay, mainly due to grade (G) 1 AST/ALT elevation; 6 (30%) required a dose reduction for lenalidomide, none for evorpacept; 1 pt discontinued treatment after 1 cycle due to G3 lenalidomide-associated myocarditis. Sixteen (80%) pts achieved CR and best overall response rate was 90%. After a median follow-up of 16 months (95% CI, 12-20 months), 1-year PFS rate was 70% and 1-year OS rate was 90%. Conclusions. The combination of evorpacept and R2 is well tolerated in pts with RR B-NHL, with similar toxicity and promising anti-tumoral activity as compared to historical CR rates with R2 alone (34%). Bulk RNA sequencing and multiplex immunofluorescence are being performed on tissue biopsies collected before and during treatment, to characterize its effects on the tumor immune microenvironment. A phase 2 study investigating its efficacy in pts with previously untreated iNHL is now enrolling. Citation Format: Paolo Strati, Lei Feng, Dai Chihara, Jason Westin, Sairah Ahmed, Luis Fayad, Jared Henderson, Jeffrey Davidson, Elizabeth McChesney, Loretta Nastoupil, Sattva Neelapu, Christopher Flowers. A phase I investigator-initiated trial of evorpacept (ALX148), lenalidomide and rituximab for patients with relapsed or refractory B-cell non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT037.

Brentuximab Vedotin Plus Ibrutinib in Relapsed and Refractory Hodgkin Lymphoma

IntroductionBrentuximab vedotin (BV) is an antibody-drug conjugate that delivers monomethyl auristatin E (MMAE) to CD30+ cells and is safe and effective in relapsed/refractory (r/r) Hodgkin lymphoma (HL). Although most patients respond to BV, only a minority will obtain a complete response (CR), and almost all patients eventually progress.Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor highly active in multiple subtypes of non-Hodgkin lymphoma; limited data exist regarding its use in HL. It irreversibly inhibits interleukin-2-inducible kinase (ITK) with Th1 based immune responses. As we previously observed preclinical synergy between ibrutinib and BV, we hypothesized ibrutinib may enhance the antitumor activity of BV in HL. We designed and conducted a phase II trial of ibrutinib plus BV in patients with R/R HL, and herein report the final primary analysis of safety and efficacy. MethodsThis was a multicenter phase II trial with a lead-in cohort in patients with r/r HL. Eligibility criteria included age ≥ 15 years with r/r HL after at least one prior line of therapy. Treatment consisted of 1.8 mg/kg BV intravenously every 3 weeks and ibrutinib 560 mg PO daily (420 mg PO daily in the lead-in cohort). Prior BV was allowed if patients were not refractory. The primary endpoint was the CR rate according to Lugano 2014. Secondary endpoints included toxicities, overall response rate (ORR), and duration of response (DOR). ResultsThe 39 patients were enrolled onto the study, of which 67% were male; the median age was 33 (range: 17-71). 38% had extranodal disease at baseline, 51% had advanced stage disease, 51% were refractory to the prior therapy, and 21% had prior BV. Of 36 patients who were evaluable for response, the CR rate was 33% and ORR 64%; median DOR was 25.5 months. Thirteen patients proceeded to autologous transplant and 3 patients proceeded to allogeneic transplant for consolidation after response. The most common adverse events were nausea (67%), peripheral neuropathy (62%), diarrhea (59%), fatigue (46%), thrombocytopenia (46%), headache (41%), rash (41%), elevated ALT (38%), anemia (36%), vomiting (36%), abdominal pain (33%), fever (33%), and hypertension (33%). Six patients experienced unacceptable toxicity, defined as Gr 3/4 non-hematologic toxicity or non-resolving Gr 3/4 hematologic toxicity including one patient who died of multiorgan failure from suspected COVID-19 infection during cycle 1. DiscussionThe combination of BV and ibrutinib was active in r/r HL; however, given significant toxicity, it cannot be recommended for future development.

1245 Malignant Meningioma Survival, Recurrence and Functional Outcomes in an International Multicenter Cohort

INTRODUCTION: Meningiomas are the most common intracranial tumor. Grade 3 (malignant) meningiomas are the most aggressive subtype and represent 1-3% of all meningiomas cases. METHODS: Demographic, clinical and histopathological data from grade 3 intracranial meningioma cases were identified in the clinical databases from seven sites in North America and Europe from 1991-2022. Summary statistics and Kaplan-Meier OS and PFS curves were generated. RESULTS: We identified 108 patients, with a median age 65 years (IQR: 52, 72) and 53.7% were female. Median OS was 109 months (95% CIs: 88, 227) and 5-year OS rate was 65% (95% CIs: 56, 76). Median PFS was 38 months (95% CIs: 24, 56) and 5-year PFS rate was 37% (95% CIs: 28, 49). Older age (=65 years old) and male sex were independent predictors of worse OS and PFS in multivariate regression analysis. Postoperative radiotherapy was independently associated with improved OS in all patients and a sensitivity analysis including only patients =65 years old. Functional status, as measured by Karnofsky performance status, was stable between preoperative (median: 80 [IQR: 70, 90]), postoperative (median: 90 [IQR: 70, 98]) and 1-year postoperative (median: 70 [IQR: 50, 80]) timepoints. CONCLUSIONS: This study provides robust survival, recurrence, and functional outcome data for malignant meningiomas in North America and Europe over a 30-year period. We demonstrate that older age and male sex are associated with worse survival and recurrence outcomes. We further affirm that adjuvant radiotherapy confers a survival benefit in the treatment of malignant meningiomas, including in patients older than 65 years. Despite concerns around surgical and radiotherapy treatment complications, functional status remains stable in the first year following treatment of malignant meningiomas.

Radiotherapy in younger patients with advanced aggressive B-cell lymphoma—long-term results from the phase 3 R-MegaCHOEP trial

The role of consolidative radiotherapy (RT) for patients with aggressive B-cell lymphoma has not been fully elucidated. The R-MegaCHOEP trial investigated the use of high-dose chemotherapy and rituximab with subsequent autologous stem cell transplantations compared to conventional immunochemotherapy (R-CHOEP) for high-risk patients up to 60 years. The study protocol included RT for patients with bulky (maximum diameter ≥7.5 cm) or extranodal disease. Two-hundred sixty-one patients were analyzed, 120 of whom underwent RT. The most frequently irradiated regions were mediastinum (n = 50) and paraaortic (n = 27). Median RT dose was 36 Gray in median fractions of 1.8 Gray. Acute toxicities were mostly mild to moderate, with only 24 and 8 grade 3 and 4 toxicities reported during RT. Patients with bulky disease who received RT showed significantly better 10-year EFS, PFS and OS (EFS: 64% vs. 35%; p < 0.001; PFS 68% vs. 47%; p = 0.003; OS: 72% vs. 59%; p = 0.011). There was no significant increase in secondary malignancies with the use of RT. RT administered for consolidation of bulky disease after immunochemotherapy improved the prognosis of young high-risk patients with aggressive B-cell lymphoma and should be considered part of first-line therapy. The trial was registered with ClinicalTrials.gov, number NCT00129090.

Favorable clinical efficacy of cytotoxic chemotherapy in patients with progressive desmoid tumors: a retrospective real-world study.

The real-world evidence about the efficacy of cytotoxic chemotherapy in desmoid tumors is still limited. We investigated the efficacy of chemotherapy in the treatment of recurrent or progressive desmoid tumors. The patients with desmoid tumors who had received cytotoxic chemotherapy between November 2007 and June 2020 in two tertiary hospitals in Korea were reviewed. A total of 25 patients were included in the analysis. The most common primary tumor site was the intra-abdominal or pelvic cavity (56%), followed by the trunk and abdominal wall (24%), extremities (16%), and head and neck (4%). Sixty percent of the patients had familial adenomatous polyposis and 76% received doxorubicin plus dacarbazine. The objective response rate and disease control rate was 64% (95% confidence interval [CI]: 40.7-82.8) and 96% (95% CI: 77.2-99.9), respectively. With the median follow-up time of 55months (95% CI: 41.0-68.2), the 3-year PFS rate was 65% (95% CI: 41.1-80.5), and the 3-year OS rate was 89% (95% CI: 63.8-97.3). Grade 3 or 4 hematologic adverse events were reported in 14 patients, all of which were manageable. Our real-world evidence suggests that doxorubicin-based cytotoxic chemotherapy can be an effective treatment option for recurrent and progressive desmoid tumors with respect to favorable clinical outcomes.

Abstract 5329: Ovarian cancer predisposes neutrophils to form neutrophil extracellular traps(NETs)

Abstract Objective: Neutrophil extracellular trap (NETs) are neutrophil-derived extracellular DNA released in response to inflammation. In contrast to their primary host-defensive role, NETs have been recently reported to promote cancer progression. The aim of this study is to investigate the role of NETs in ovarian cancer progression. Method: The clinical data of ovarian cancer patients who underwent primary surgery at Osaka University Medical Hospital were retrospectively reviewed (n=340). The relationship between neutrophilia, peritoneal dissemination and prognosis were analyzed. Prior to initial treatment, peripheral blood was obtained from newly diagnosed ovarian cancer patients and examined for CBC and granulocyte-colony stimulating factor (G-CSF) concentration by ELISA. To evaluate NETs formation capacity, isolated neutrophils were stimulated with G-CSF and incubated in vitro to monitor NETs formation. The ascites was collected at the initial surgery and assessed for G-CSF concentration and for neutrophils population using flow cytometry. The omental tissues were pathologically examined for NETs using H&amp;E-staining and immunostaining with anti-Citrullinated Histon3 (CitH3) antibody. To test NETs induction capacity, we treated human peripheral blood neutrophils with the conditioned media from 20 ovarian cancer cell lines and the serum from ovarian cancer patients. Then human ovarian cancer OVCAR8 cells were co-cultured with NETs to evaluate the effect of NETs on cancer cell adhesion. Results: Neutrophilia (neutrophils&amp;gt;7000/µl) was found in 39 patients (39/340,11.5%). Patients with neutrophilia were associated with advanced disease accompanied by peritoneal dissemination and compromised survival compared to patients without neutrophilia (5-year PFS 40.0 vs 59.9 %, p 0.0027). In these patients, serum G-CSF was upregulated. Neutrophils from ovarian cancer patients formed NETs significantly earlier than those from benign tumor patients. Ovarian cancer patients with neutrophilia showed elevated G-CSF concentration and increased neutrophils proportion in their ascites. Omental tissues from patients with neutrophilia showed NETs foci close to the disseminated lesions. G-CSF strongly induced neutrophils to form NETs in vitro, which was observed in some conditioned media from ovarian cancer cell lines and serum from ovarian cancer patients as well. The adhesion of ovarian cancer cell was increased by co-incubation with NETs. Conclusion: Neutrophilia is associated with peritoneal dissemination and poor prognosis in ovarian cancer. One of the underlying mechanism of neutrophilia is upregulated G-CSF, which stimulate neutrophils to form NETs. NETs may have a causative effect on ovarian cancer dissemination. Citation Format: Gaku Yamamoto, Mahiru Kawano, Michiko Bun, Koutaro Shimura, Aska Toda, Koji Nakamura, Yasuto Kinose, Michiko Kodama, Kae Hashimoto, Kenjiro Sawada, Tadashi Kimura. Ovarian cancer predisposes neutrophils to form neutrophil extracellular traps(NETs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5329.

Brentuximab vedotin and chemotherapy in relapsed/refractory Hodgkin lymphoma: a propensity score–matched analysis

AbstractSeveral single-arm studies have explored the inclusion of brentuximab vedotin (BV) in salvage chemotherapy followed by autologous stem cell transplantation (ASCT) for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). However, no head-to-head comparisons with standard salvage chemotherapy have been performed. This study presents a propensity score–matched analysis encompassing individual patient data from 10 clinical trials to evaluate the impact of BV in transplant-eligible patients with R/R cHL. We included 768 patients, of whom 386 were treated with BV with or without chemotherapy (BV cohort), whereas 382 received chemotherapy alone (chemotherapy cohort). Propensity score matching resulted in balanced cohorts of 240 patients each. No significant differences were observed in pre-ASCT complete metabolic response (CMR) rates (P = .69) or progression free survival (PFS; P = .14) between the BV and chemotherapy cohorts. However, in the BV vs chemotherapy cohort, patients with relapsed disease had a significantly better 3-year PFS of 80% vs 70%, respectively (P = .02), whereas there was no difference for patients with primary refractory disease (56% vs 62%, respectively; P = .67). Patients with stage IV disease achieved a significantly better 3-year PFS in the BV cohort (P = .015). Post-ASCT PFS was comparable for patients achieving a CMR after BV monotherapy and those receiving BV followed by sequential chemotherapy (P = .24). Although 3-year overall survival was higher in the BV cohort (92% vs 80%, respectively; P < .001), this is likely attributed to the use of other novel therapies in later lines for patients experiencing progression, given that studies in the BV cohort were conducted more recently. In conclusion, BV with or without salvage chemotherapy appears to enhance PFS in patients with relapsed disease but not in those with primary refractory cHL.

Real-World Outcome of Treatment with Single-Agent Ibrutinib in Italian Patients with Chronic Lymphocytic Leukemia: Final Results of the EVIdeNCE Study.

Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with CLL receiving single-agent ibrutinib in first line (1L, n = 118), 2L (n = 127) and ≥3L (n = 64) in the prospective, real-world, Italian EVIdeNCE study. After a median follow-up of 23.9 months, 29.8% of patients discontinued ibrutinib (1L: 24.6%, 2L: 29.9%, ≥3L: 39.1%), mainly owing to adverse events (AEs)/toxicity (14.2%). The most common AEs leading to discontinuation were infections (1L, ≥3L) and cardiac events (2L). The 2-year retention rate was 70.2% in the whole cohort (1L: 75.4%, 2L: 70.1%, ≥3L: 60.9%). The 2-year PFS and OS were, respectively, 85.4% and 91.7% in 1L, 80.0% and 86.2% in 2L, and 70.1% and 80.0% in ≥3L. Cardiovascular conditions did not impact patients' clinical outcomes. The most common AEs were infections (30.7%), bleeding (12.9%), fatigue (10.0%), and neutropenia (9.7%), while grade 3-4 atrial fibrillation occurred in 3.9% of patients. No new safety signals were detected. These results strongly support ibrutinib as a valuable treatment option for CLL.

Debulking hepatectomy for colorectal liver metastasis: Analysis of risk factors for progression free survival

BackgroundThe study explores the role of liver debulking surgery in cases of unresectable colorectal liver metastases (CRLM), challenging the traditional notion that surgery is not a valid option in such scenarios. Materials and methodsPatients with advanced but resectable disease who underwent surgery with a curative intent (Group I) and those with advanced incompletely resectable disease who underwent a “debulking” hepatectomy (Group II) were compared. ResultsThere was no difference in the intra-operative and post-operative results between the two groups. The 3-year and 5-year OS rates were 69% and 47% for group 1 vs 64% and 35% for group 2 respectively (p = 0.14). The 3-year and 5-year PFS rates were 32% and 21% for group 1 vs 12% and 8% for group 2 respectively (p = 0.009). Independent predictors of PFS in the debulking group were bilobar metastases (HR = 2.70; p = 0.02); the presence of extrahepatic metastasis (HR = 2.65, p = 0.03) and the presence of more than 9 metastases (HR = 2.37; p = 0.04). Iterative liver surgery for CRLM was a significant protective factor (HR = 0.34, p = 0.04). ConclusionAn aggressive palliative surgical approach may offer a survival benefit for selected patients with unresectable CRLM, without increasing the morbidity. The decision for surgery should be made on a case-by-case basis.

Perioperative chemotherapy with docetaxel plus oxaliplatin and S-1 (DOS) versus oxaliplatin plus S-1 (SOX) for the treatment of locally advanced gastric or gastro-esophageal junction adenocarcinoma (MATCH): an open-label, randomized, phase 2 clinical trial

BackgroundIt remains unclear whether addition of docetaxel to the combination of a platinum and fluoropyrimidine could provide more clinical benefits than doublet chemotherapies in the perioperative treatment for locally advanced gastric/gastro-esophageal junction (LAG/GEJ) cancer in Asia. In this randomized, phase 2 study, we assessed the efficacy and safety of perioperative docetaxel plus oxaliplatin and S-1 (DOS) versus oxaliplatin plus S-1 (SOX) in LAG/GEJ adenocarcinoma patients.MethodsPatients with cT3–4 Nany M0 G/GEJ adenocarcinoma were randomized (1:1) to receive 4 cycles of preoperative DOS or SOX followed by D2 gastrectomy and another 4 cycles of postoperative chemotherapy. The primary endpoint was major pathological response (MPR).ResultsFrom Aug, 2015 to Dec, 2019,154 patients were enrolled and 147 patients included in final analysis, with a median age of 60 (26–73) years. DOS resulted in significantly higher MPR (25.4 vs. 11.8%, P = 0.04). R0 resection rate, the 3-year PFS and 3-year OS rates were 78.9 vs. 61.8% (P = 0.02), 52.3 vs. 35% (HR 0.667, 95% CI: 0.432–1.029, Log rank P = 0.07) and 57.5 vs. 49.2% (HR 0.685, 95% CI: 0.429–1.095, Log rank P = 0.11) in the DOS and SOX groups, respectively. Patients who acquired MPR experienced significantly better survival. DOS had similar tolerance to SOX.ConclusionsPerioperative DOS improved MPR significantly and tended to produce longer PFS compared to SOX in LAG/GEJ cancer in Asia, and might be considered as a preferred option for perioperative chemotherapy and worth further investigation.

Impact of melphalan day -1 vs day -2 on outcomes after autologous stem cell transplant for multiple myeloma.

Melphalan is the most common conditioning regimen used prior to autologous stem cell transplant (ASCT); however, there are varying data on optimal melphalan timing prior to transplant for best safety and efficacy. Historically, ASCT conditioning consisted of melphalan 200 mg/m2 on day 2 (D-2) (48 h prior to ASCT), but many institutions have since adopted a melphalan protocol with administration on day 1 (D-1) (24 h prior to SCT) or split dosing over the 2 days. The optimal timing of melphalan has yet to be determined. In this single-center retrospective study, we analyzed transplant outcomes for patients between March 2011 and September 2020 admitted for high-dose, single-agent melphalan 200 mg/m2 on D-1 vs. D-2. The primary outcomes were time to neutrophil and platelet engraftment. Secondary outcomes include incidence of hospital readmission within 30 days, 2-year progression-free survival, and 2-year overall survival. A total of 366 patients were studied (D-2 n = 269 and D-1 n = 97). The incidence of high-risk cytogenetics was similar between the two groups (37% vs. 40%). Median days to absolute neutrophil count engraftment was similar at 11 days in the D-2 and D-1 cohort (n = 269, range 0-14, IQR 11-11 vs. n = 97, range 0-14, IQR 11-12). Median days to platelet engraftment >20,000/mcL was 18 days for D-2 melphalan (range: 0-28, IQR 17-20) versus 19 days for D-1 melphalan (range: 0-32, IQR 17-21). Overall survival at 2 years post-transplant was similar in both cohorts (94%; p = 0.76), and PFS was 70% in D-2 compared with 78% in D-1 (p = 0.15). In a multivariable model including age and performance status, hospital readmission within 30 days of transplant was higher in the D-1 cohort (odds ratio 1.9; p = 0.01). This study demonstrates similar neutrophil and platelet engraftment in D-1 and D-2 melphalan cohorts with similar 2-year PFS and OS. Either D-2 or D-1 melphalan dosing schedule is safe and effective.