Significant Improvement In Progression-free Survival Research Articles

Effectiveness of c-TACE Combined With Sorafenib Versus c-TACE Monotherapy in Advanced Hepatocellular Carcinoma: A Retrospective Study.

Hepatocellular carcinoma (HCC) has insidious onset. Most HCC patients are in advanced stage at the time of initial diagnosis, and the treatment response is poor. The purpose of this study was to compare the clinical effectiveness of conventional transcatheter arterial chemoembolization (c-TACE) combined with sorafenib versus c-TACE monotherapy in the treatment of advanced HCC. A retrospective analysis was performed on patients with advanced HCC (stage C based on the Barcelona Clinic Liver Cancer staging system) admitted to the Affiliated Hospital of Southwest Medical University from December 9, 2013, to February 25, 2021. After screening for inclusion and exclusion criteria, 120 patients were finally included, including 60 patients in the c-TACE group and 60 patients in c-TACE + sorafenib group. There were no statistically significant differences in general data between the 2 groups before treatment. Overall survival (OS) and progression-free survival (PFS) were compared between the 2 groups, and prognostic factors were assessed by Cox proportional risk model. The study found that median PFS was 7.37 months in the c-TACE + sorafenib group and 5.97 months in c-TACE group, a statistically significant difference (χ2 = 5.239, P = .022 < .05). The median OS was 22.9 months in the combination group and 12.1 months in c-TACE monotherapy group, also a statistically significant difference (χ2 = 5.848, P = .016 < .05). The Cox proportional risk model found that c-TACE number and presence of ascites were common risk factors among patients in both groups (P < .05). c-TACE + sorafenib was superior to c-TACE alone in the treatment of advanced HCC and yielded significant improvements in PFS and OS in our study. The number of c-TACE and presence of ascites were common risk factors affecting the survival of patients in the 2 groups.

Zolbetuximab: An Investigational First-Line Treatment for CLDN18.2-positive, HER2-negative Gastric and Gastro-oesophageal Junction Cancer

Biomarker-based targeted therapies have changed the cancer treatment paradigm. While early-stage gastric and gastro-oesophageal junction (GOJ) adenocarcinomas can benefit from surgery, advanced presentations of these diseases have limited therapeutic options and poor prognoses. Zolbetuximab, a chimeric monoclonal antibody targeting Claudin 18.2 (CLDN18.2), exerts its effect through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. It has emerged as a promising treatment for advanced gastric/GOJ cancer. Clinical trials have assessed its efficacy and safety across multiple phases, demonstrating significant improvements in progression-free survival and overall survival. The safety profile of zolbetuximab primarily includes manageable gastrointestinal adverse events, namely nausea and vomiting. Zolbetuximab's potential extends beyond its primary indication, with on-going trials exploring its efficacy in other CLDN18.2-expressing malignancies, such as pancreatic adenocarcinoma. This review highlights zolbetuximab's potential as a first-line therapy for CLDN18.2-positive, HER2-negative gastric and GOJ adenocarcinomas, shedding light on its mechanism of action, clinical trial results, safety profile and current treatment landscape.

Ten-year treatment outcomes of consolidation hyperthermic intraperitoneal chemotherapy for ovarian cancer (HIPEC-KOV-03R).

We aimed to evaluate the long-term efficacy of consolidation hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with primary epithelial ovarian cancer. This retrospective cohort study included patients who underwent second-look surgery either with or without HIPEC after having complete or partial response to primary cytoreductive surgery and adjuvant platinum-based chemotherapy between January 1991 and December 2003 at Seoul St. Mary's Hospital. The 10-year progression-free survival (PFS), overall survival (OS), and toxicity within postoperative 28 days were investigated. A total of 87 patients were identified, 44 (50.6%) received second-look surgery with HIPEC whereas 43 (49.4%) received only second-look surgery. The 10-year PFS and OS were significantly longer in the HIPEC group compared with the control group (PFS, 53.6% vs. 34.9%, log-rank p=0.009; OS, 57.0% vs. 34.5%, log-rank p=0.025). Multivariable analysis identified HIPEC as an independent favorable prognostic factor for PFS (adjusted hazard ratio [HR]=0.42; 95% confidence interval [CI]=0.23-0.77; p=0.005) but not for OS (adjusted HR=0.58; 95% CI=0.32-1.07; p=0.079). The more common adverse events in the HIPEC group were thrombocytopenia (90.9% vs. 68.3%, p=0.005), elevated liver enzymes (65.9% vs. 29.3%, p=0.002), and wound complications (18.2% vs. 2.4%, p=0.032). However, these adverse events were reversible and did not delay subsequent consolidation chemotherapy. The consolidation HIPEC demonstrated a significant improvement in 10-year PFS but not OS, with acceptable toxicity in patients with primary epithelial ovarian cancer. Further randomized controlled trials are warranted to confirm these results.

Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study

AbstractThis global phase 3 study compared lisocabtagene maraleucel (liso-cel) with a standard of care (SOC) as second-line therapy for primary refractory or early relapsed (≤12 months) large B-cell lymphoma (LBCL). Adults eligible for autologous stem cell transplantation (ASCT; N = 184) were randomly assigned in a 1:1 ratio to liso-cel (100 × 106 chimeric antigen receptor–positive T cells) or SOC (3 cycles of platinum-based immunochemotherapy followed by high-dose chemotherapy and ASCT in responders). The primary end point was event-free survival (EFS). In this primary analysis with a 17.5-month median follow-up, median EFS was not reached (NR) for liso-cel vs 2.4 months for SOC. Complete response (CR) rate was 74% for liso-cel vs 43% for SOC (P < .0001) and median progression-free survival (PFS) was NR for liso-cel vs 6.2 months for SOC (hazard ratio [HR] = 0.400; P < .0001). Median overall survival (OS) was NR for liso-cel vs 29.9 months for SOC (HR = 0.724; P = .0987). When adjusted for crossover from SOC to liso-cel, 18-month OS rates were 73% for liso-cel and 54% for SOC (HR = 0.415). Grade 3 cytokine release syndrome and neurological events occurred in 1% and 4% of patients in the liso-cel arm, respectively (no grade 4 or 5 events). These data show significant improvements in EFS, CR rate, and PFS for liso-cel compared with SOC and support liso-cel as a preferred second-line treatment compared with SOC in patients with primary refractory or early relapsed LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03575351.

Efficacy of Osimertinib Combined with Bevacizumab in Advanced Non-small Cell Lung Cancer Patients with Acquired EGFR T790M Mutation

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) capable of overcoming non-small cell lung cancer (NSCLC) with EGFR T790M mutation. Although the addition of bevacizumab to 1st generation EGFR-TKIs confers a significant improvement in progression-free survival (PFS) in treatment-naive EGFR mutant NSCLC patients, osimertinib plus bevacizumab combination failed to show prolongation in the phase 2 study WJOG8715L. Data of such combination in Chinese patients are still lacking. This study aimed to explore the efficacy of the addition of bevacizumab to osimertinib as second-line therapy in real-world data, and to evaluate the role of anti-angiogenesis plus osimertinib combination therapeutic strategies in pretreated Chinese NSCLC patients with acquired EGFR T790M mutation. A total of 42 advanced NSCLC patients with acquired EGFR T790M mutation after prior EGFR-TKIs treatment were collected between January 2020 to August 2021, with 16 cases treated with osimertinib plus bevacizumab and 26 cases treated with osimertinib. The treatment effect of patients were analyzed. The objective response rate (ORR) in combination group and osimertinib group were 43.8% and 50.0% respectively (P=0.694). No statistically significant difference in median PFS (14.0 mon vs 13.0 mon, P=0.797) and overall survival (OS) (29.0 mon vs 26.0 mon, P=0.544) between the combination group and osimertinib group were observed. Prior history of bevacizumab was identified as an independent predictor of PFS (P=0.045) and OS (P=0.023). Our study demonstrated that adding bevacizumab to osimertinib could not show advantages in PFS and OS in pretreated NSCLC patients harboring EGFR T790M-mutation.

EE139 Cost-Effectiveness of Poly ADP-Ribose Polymerase (PARP) Inhibitors in Cancer Treatment: A Systematic Review

PARP inhibitors have shown significant improvement in progression-free survival, but their costs cast a considerable financial burden. In line with value-based oncology, it is important to evaluate whether drug prices justify the outcomes. This study aimed to systematically evaluate PARP inhibitors on: 1) cost-effectiveness against standard care, 2) impact on cost-effectiveness upon stratification for genetic characteristics, and 3) identify factors determining their cost-effectiveness, in four cancer types.

Complete response in patient with liver metastasis of HER2-positive breast cancer following therapy with margetuximab: a case report.

Metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer has a poor prognosis and few effective targeted therapies. However, several anti-HER2 agents are emerging in conjunction with chemotherapy, which may lead to increased rates of pathological complete response in patients with HER2-positive metastatic breast cancer. Among them, margetuximab demonstrated a significant improvement in progression-free survival compared with trastuzumab, when combined with chemotherapy in pretreated patients. Here we present a case of a 67-year-old female patient who was diagnosed with HER2-positive, histological grade III and invasive ductal carcinoma of the left breast in September 2018. She received postoperative adjuvant therapy with EC-TH plus radiotherapy, followed by therapy with HER2-targeted trastuzumab for 1 year (till December 2019). In May 2020, routine reexamination showed a supraclavicular lymph node and bone metastasis. Patient was then treated with pyrotinib, capecitabine and bisphosphonate for a period of 3 months. In December 2020, liver MRI revealed multiple liver metastases. The patient received eight cycles of second-line therapy (vinorelbine plus margetuximab) from January 2021. Since the ninth cycle, the patient was continued with only margetuximab. In March 2021, MRI showed a 70% decrease in the liver metastasis lesions. By June 2021, liver lesions were totally disappeared. During therapy, patient experienced only grade-1 anemia. This case demonstrates that margetuximab plus chemotherapy is safe and might bring clinical benefits for patients with HER2-positive breast cancer with liver metastasis. Further studies evaluating the efficacy and safety of margetuximab in Chinese HER2-positive breast cancer patients are needed.

Carfilzomib, Lenalidomide and Dexamethasone (KRd) Vs Bortezomib, Lenalidomide, and Dexamethasone (VRd) As Induction Therapy in Newly Diagnosed High-Risk Multiple Myeloma

Background: Bortezomib, lenalidomide, dexamethasone (VRd) and carfilzomib, lenalidomide, dexamethasone (KRd) are standard induction regimens for the treatment of newly diagnosed multiple myeloma (NDMM). The phase III ENDURANCE trial excluded patients with high-risk NDMM (HR-NDMM) and included patients with no intention for immediate autologous stem cell transplant (ASCT) (Kumar SK, et al. Lancet Oncol 2020). Herein, we examined outcomes associated with KRd and VRd induction in the management of HR-NDMM. Methods: We conducted a retrospective chart review study with 154 consecutive HR-NDMM patients treated with VRd and KRd at MSKCC between 1/1/2015 to 12/31/2019. Only patients with high-risk (HR) cytogenetics defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p) were included. The cutoff date for analysis was 8/18/21. Early transplant was defined as ASCT within 6 months of completing induction. Primary endpoint was progression-free survival (PFS). Discrete patient characteristics were summarized by frequency (percentage) and continuous characteristics were summarized by median (IQR). PFS and overall survival (OS) were evaluated by Kaplan-Meier method. Multivariable Cox models were fitted with pre-specified clinical parameters including age, cardiac history, R-ISS stage, best response to induction, early ASCT (both time dependent covariates), and induction regimen. Results: Baseline characteristics of the 67 VRd and 87 KRd treated patients are summarized in table 1. There were 51 (76%) patients in the VRd group and 63 (72%) patients in the KRd group with 1 HR cytogenetic abnormality. Sixteen (24%) and 24 (28%) patients in the VRd and KRd groups, respectively, had ≥2 HR cytogenetic abnormalities. Among the HR-NDMM patients, 32 VRd- and 48 KRd-treated patients received early ASCT. Overall response rate by the end of induction was 93% and 98% for VRd and KRd, respectively, including 66% with ≥VGPR in the VRd group and 80% in the KRd group. Median follow-up for the entire patient population was 42.5 (IQR, 37.5-50) months with 47.9 (42.5-53.9) months for the VRd group and 37.6 (35-50) months for the KRd group. The median PFS for HR-NDMM patients treated with VRd induction was 42.6 months (95%CI, 32.8-62) and was NR (95%CI, 45.5-NR) for the KRd group (HR=1.84; 95%CI, 1.11-3.06; P=0.02) (Fig. 1). We conducted a multivariate analysis for important clinical variables that may affect survival outcomes. Multivariable analysis for PFS showed that KRd induction (HR=1.80; 95%CI, 1.05-3.10; P=0.033) and R-ISS Stage I compared to R-ISS Stage II (HR=2.67; 95%CI, 1.33-5.38; P=0.006) and R-ISS Stage III (HR=3.51; 95%CI, 1.02-12.07; P=0.046) were associated with better PFS. Early ASCT was not associated with improvement of PFS on multivariable analysis (P=0.30). Age, cardiac history, and achieving CR/sCR or VGPR/PR compared to <PR as the best response to induction did not have a statistically significant effect on PFS. We conducted a subgroup analysis of HR-NDMM patients who received early ASCT (N=79). At median follow-up since time of transplant of 43.5 months for VRd and 28.4 months for KRd, the estimated 3-year PFS since the time of transplant was 55% (95%CI, 38-79) and 67% (95%CI, 52-85) for VRd and KRd-treated patients, respectively (HR=1.65; 95%CI, 0.78-3.50; P=0.20). The estimated 3-year OS from the time of transplant was 80% (95%CI, 66-81) for the VRd group and 91% (95%CI, 81-100) for the KRd group, respectively (HR=2.45; 95%CI, 0.60-10.0; P=0.20). Conclusion: There was a significant improvement in PFS among HR-NDMM patients who received KRd compared to VRd induction. In patients who received early ASCT, we did not observe a statistically significant difference in PFS or OS between the two induction regimens, but this analysis is subject to inherent selection bias. Until results from prospective randomized studies are available for HR-NDMM patients, the use of various induction regimens in transplant-eligible patients opting for early transplant should be tailored to each patient. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

What Is the Benefit of Autologous Stem Cell Transplantation in Multiple Myeloma Beyond the Age of 65? Inputs from Real-World Data in the Emmy Cohort

Background The management of newly diagnosed multiple myeloma (NDMM) patients under 70 years of age, in good health condition and without comorbidities, is based on an induction therapy followed by high-dose therapy with autologous stem cell transplantation (ASCT) and maintenance (1). Several studies have demonstrated this regimen to be effective up to 65 years of age (2). Beyond this age, patients are often excluded from clinical trials and few real-world evidence studies are available. The EMMY study, a large-scale real-world study designed to assess the epidemiology and real-life management of MM, describes the use of ASCT in patients aged of 65 and over and its efficacy compared to other treatments. Methods EMMY is a non-interventional, prospective study conducted in 72 IFM (Intergroupe Francophone du Myélome, sponsor) centers in France. Any patient initiating treatment for MM over a 3-month observation period, from October to December, is included, since 2017. It is a dynamic cohort with the inclusion of 800 to 1000 additional patients each year (3616 patients included at the end of 2020). Data are updated annually from hospital records up to 2021. NDMM patients aged 65 years and over, who received a front-line therapy with ASCT (ASCT+), were identified and described. Progression-free survival (PFS) (median and rates at 36 and 48 months (m)), time to next treatment (TTNT) (median and rates at 36m and 48m) and overall survival (OS) rates at 36m and 48m were described for ASCT+ patients ≥65 years and compared to ASCT+ patients <65 years identified in EMMY (Wilcoxon test). ASCT+ patients ≥65 years were also compared with non-autologous transplant patients (ASCT-) of the same age ([65-75[ years). Same analyses were conducted for the subgroup of ASCT+ / ASCT- patients aged of 66-70 years. Results Among the 1597 NDMM patients enrolled in EMMY, 156 NDMM patients ≥65 years of age received a first-line therapy with ASCT; 129 (82.7%) had less than 70 years and 27 beyond (17.3%). Patients were male (55.1%), without comorbidities (72.4%) with an ECOG of 0 or 1 (89.4%) and an ISS score of 1, 2, 3 for 30.3%, 39.4% and 30.3% of them. For those patients, mPFS was estimated at 47.7m (95 CI% [34.4 to not reached]) with 36m and 48m PFS rates estimated at 56.1% (95 CI% [46.2; 66.0]) and 48.6% (95 CI% [37.0; 60.3]). mTTNT was not reached while 36m and 48m TTNT rates were 67.6% (95 CI% [57.7; 77.4]) and 57.4% (95 CI% [45.3; 69.4]). Regarding OS, 36m and 48m rates were 96.2% (95 CI% [92.8; 99.5]) and 89.3% (95 CI% [81.0; 97.6]). Survival outcomes for ASCT+ patients aged ≥65 years did not differ from those for ASCT+ patients aged <65 years (n=397 in EMMY) for PFS (p=0.32), TTNT (p=0.54), and OS (p=0.54). ASCT+ patients aged ≥ 65 years had similar characteristics (M/F ratio, ECOG, ISS, comorbidities) than ASCT+ patients aged <65 years. Compared with ASCT- patients of same age (n=397), ASCT+ patients aged ≥65 years had higher survival outcomes with a significant improvement in PFS (mPFS of 47.7m vs. 19.4m and 36m rates of 56.1% vs. 32.8%, p<0.0001, Figure 1), in TTNT (mTTNT not achieved vs 23.4m in ASCT- patients and 36m rates of 67.6% vs. 34.7%, p<0.0001); and in OS (36m rates of 96.5% vs. 74.0%, p=0.0013). ASCT+ patients aged ≥ 65 years had a median age of 67.5 years (vs. 70.8 years), ECOG 0-1 for 89.4% (vs. 69.0%), comorbidities for 27.6% (vs. 44.3%) and ISS II or III for 69.7% (vs. 76.4%) compared to ACST- patients aged ≥65 years. Same comparisons performed with the 66-70 years subgroup of ASCT+ (n=105) and ASCT- (n=192) patients confirmed previous survival outcomes results in terms of PFS (mPFS of 47.5m vs 20.6m, p=0.0004), TTNT (p<0.0001) and OS (p=0.0002). Conclusion These results are among the first estimates of the higher efficacy of ASCT in selected patients aged 65 years and over. Almost half patients (46.2%) up to 70 years of age received ASCT as first-line therapy, less frequently (about 10%) beyond. Although the use of ASCT is usually reserved to healthy patients, its clinical benefit over 65 years is significant in terms of survival and equivalent to that observed in younger patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Carfilzomib and Lenalidomide for the Treatment of Primary Plasma Cell Leukemia: Final Results of the Prospective Phase 2 EMN12/HOVON-129 Study for Patients Aged ≥66 Years

Introduction. Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell disorder with a very poor prognosis, requiring urgent action to prevent early mortality and to control the disease and complications. The EMN12/HOVON-129 study assessed the efficacy of carfilzomib and lenalidomide as part of first-line therapy in pPCL. The trial enrolled patients (pts) aged 18 years and older, with different treatment for those 18-65 and ≥66 years. Here we report the results for pts in the age-group ≥66 years. Methods. The EMN12/HOVON-129 study is a prospective, non-randomized, phase 2, multicenter study for previously untreated pPCL pts. Inclusion criteria were newly diagnosed pPCL (in this study defined as >2x109/L circulating monoclonal plasma cells and/or plasmacytosis >20% of the differential white cell count) and WHO performance status 0-3. Main exclusion criteria were severe cardiac or pulmonary dysfunction and creatinine clearance <15 ml/min. There were no restrictions based on blood counts. Pts ≥66 years received induction therapy with eight 28-day cycles of carfilzomib-lenalidomide-dexamethasone (KRd; carfilzomib 20/36 mg/m2 on days 1,2,8,9,15,16; lenalidomide 25 mg on days 1-21; dexamethasone 20 mg on days 1,2,8,9,15,16,22,23), followed by maintenance with carfilzomib (27 mg/m2 on days 1,2,15,16 for the first twelve cycles; then 56 mg/m2 on days 1,15) and lenalidomide (10 mg on days 1-21/28 days) until progression. The primary endpoint was progression-free survival (PFS); secondary endpoints were response rate, overall survival (OS), and toxicity. Results. From October 2015 to August 2021, we enrolled 61 pts with pPCL: 36 aged ≤65 years and 25 aged ≥66 years. Among the 25 pts aged ≥66 years, median age was 71 years (range 66-84); 68% had bone disease; and WHO performance status was 2 in 24% and 3 in 16% of pts. Median plasma cell percentage in bone marrow biopsy was 80% (10-100). Median peripheral blood plasma cell count was 3.8x109/L (range 2.0-52); median platelet count was 142x109/L (range 13-384); and median GFR was 56 ml/min (range 24-95). Most of pts had high-risk disease features, as proved by elevated LDH in 52% and high frequency of poor-risk genetic lesions (del(17p) in 20%, t(4;14) in 4%, t(14;16) in 4%, and gain/amp(1q) in 48%). In addition, 12% of pts had extramedullary plasmacytomas. ISS stage III was present in 68% and Revised ISS stage III in 40%. At the data cut-off (July 1, 2022), among the 25 pts, 17 (68%) received the planned 8 cycles of induction treatment, achieving ≥partial response (PR) in 80%, ≥very good (VG)PR in 68%, and ≥complete response (CR) in 32% of pts. Sixteen pts (64%) received maintenance treatment. Best response on protocol was ≥PR in 80%, ≥VGPR in 68% and ≥CR in 36%; 3 out of 4 pts in CR who could be evaluated for minimal residual disease (MRD) achieved MRD negativity (10-5) by flow cytometry. With a median follow-up of 24.6 months (range 7.9-59.6), the median PFS was 13.8 months (95% CI 9.2-35.5), which was sufficient to reject our null hypothesis (median PFS=6.5 months). With 16 pts having died (8 due to disease progression, 2 unknown, 1 pneumonia, 1 sepsis, 1 systemic aspergillus infection, 1 small intestinal SPM, 1 disseminated intravascular coagulation, 1 respiratory failure due to COPD exacerbation), median OS was 24.8 months (95% CI 14-not reached [NR]; Figure). Adverse events mainly occurred during the first two cycles of KRd and decreased thereafter. Overall, 36% of pts had grade (G)3 and another 36% G4 adverse events. G3 and G4 hematologic toxicity rates were 8% and 12%, respectively. Infections (20% and 16%) and respiratory events (16% and 4%) were the most common G3 and G4 non-hematologic toxicities. Twenty-two pts (88%) discontinued protocol treatment, mainly because of progression (13 pts, 59%). Conclusions. KRd is a potent treatment strategy to control disease in pPCL pts over 65 years of age, with not negligible, but generally manageable, treatment-related toxicities. Of note, along with a significant improvement of PFS, median OS substantially doubled compared to what has been reported in recent retrospective studies and, particularly, in the only other prospective trial (with the doublet lenalidomide-dexamethasone) so far conducted in transplant ineligible, elderly pts with pPCL (Musto P et al. Leukemia. 2014;28:222-5). This trial was registered at www.trialregister.nl (until June 2022) and https://trialsearch.who.int/ as NTR5350. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Survival of Patients with Primary Mediastinal B-Cell Lymphoma Treated By Immunochemotherapy with or without Radiotherapy

Introduction: Primary mediastinal B-cell lymphoma (PMBL) is B-non-Hodgkin lymphoma subtype with unique clinical and biological characteristics mostly affecting younger patients. The current treatment standard is based on combination of rituximab and anthracycline based chemotherapy (R-CHT), either standard (R-CHOP) or intensified (DA-EPOCH-R). Radiotherapy (RT) consolidation has been standard of care for a long time, but its role is currently unclear, especially in the context of PET/CT guided therapy and long term toxicity prevention considering young patient population (Hayden at al.2020, Giulino-Roth 2018). In this analysis we evaluate the survival benefit of RT consolidation in patients with PMBL achieving PET negative (PET-neg) response after R-CHT. Methods: Patients with confirmed diagnosis of PMBL observed in NiHiL project (Gov Trial No: NCT03199066) were analysed. All patients were treated by R-CHT; PET/CT was performed at the end of the immunochemotherapy. The treatment response was evaluated according to Cheson 2007 criteria. Only patients achieving PET negativity were included in primary analysis. Results: The study included 230 patients out of whom 133 (57.8%) were women. Median age was 37 years (range 19-79); localised stage (I-II) was observed in 165 patients (71.7%) and low or low-intermed IPI in 189 patients (82.2%). The diagnosis was confirmed by central pathologist in all cases. Patients were treated by R-CHT, mostly R-CHOP (52.2%) and R-CHOEP-like (25.2%; i.e. R-CHOEP or DA-EPOCH-R); other intensive regimens, incl. platinum were used in 19.6% of patients; 48 patients (20.8%) received ASCT as part of first line induction. PET/CT was performed at the end of R-CHT (including ASCT); 174 patients (75.7%) achieved PET-neg remission at the end of the immunochemotherapy, 56 (24.3%) were PET positive (PET-pos). After reaching PET negativity, radiotherapy was performed in 68 patients (39.1%) with median dose of 36Gy (range 20-42Gy); 106 patients were not consolidated by RT and observed (OBS). There was higher incidence of bulky disease and B-symptoms in RT group (57% vs 47% and 57% vs 48% resp.) without reaching statistical significance. Median follow up was 5.9 years. OS and PFS probability at 6y were 90.5% and 83.6% resp. for the whole cohort. RT consolidation in PET-negative subgroup led to a significant improvement (p=0.039) in PFS at 6y with 95% (n=68) vs 85.3% in OBS group (n=106). This was, however, not transformed into the OS difference (94.5% vs 92.1% probability at 6y for RT vs OBS; HR 1.64, CI95% 0.52-5.8), figure 1. In subgroup of patients treated by R-CHOP, there was an insignificant trend for better PFS probability in RT group (HR 2.41, 95%CI 0.71-6.92, p=0.17). This was not reflected in any OS difference. The outcome of patients who reached PET negativity by R-CHOEP was the same regardless of the radiotherapy use. Conclusion: Our analysis of retrospectively recorded patients shows that skipping RT in PET-neg PMBL patients at the end of immunochemotherapy does not hamper overall survival. There was borderline improvement of PFS. The patient cohorts with different chemotherapy regimens were not big enough to analyse the RT significance. However, data observed in patient subpopulation treated by CHOEP-like regimen confirm already published observations (Dunleavy et al. 2013) concluding possible RT oblivion after intensified immunochemotherapy. Therefore, the choice between radiotherapy consolidation vs observation in PET negative patients should be discussed with the patient especially when less intensive regimen (R-CHOP) is used. Acknowledgement: This work was supported by Cooperatio Program - research area Oncology and Hematology and by research grant NU21-03-00411 Figure 1. Survival analysis of patients reaching PET negative remission after chemotherapy (n=174) shows improvement in progression free survival (PFS) for patients consolidated with radiotherapy (RT), however without reflection in overall survival (OS). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Systematic Review and Network Meta-Analysis of Frontline Targeted Therapy in Chronic Lymphocytic Leukemia Shows Comparable Efficacy but Distinct Toxicity

Introduction: Targeted therapies inhibiting Bruton Tyrosine Kinase (BTK) (ibrutinib, acalabrutinib, and zanubrutinib) and Bcl-2 (venetoclax) have improved survival when given first line (1L) to patients with chronic lymphocytic leukemia (CLL). However, no head-to-head trials of 1L targeted therapies exist to guide clinicians on selection of optimal therapy for their patients. We performed a systematic review and network meta-analysis (NMA) to understand the relative efficacy and toxicity of 1L CLL regimens, including newer regimens of ibrutinib/venetoclax (IV) and zanubrutinib not previously assessed in NMA. Methods: We performed a systematic literature search from 2009-2022 for randomized trials of treatment-naïve adults with CLL who were deemed unfit due to age or comorbidities. Endpoints were progression free survival (PFS) at 24 and 48 months, overall response rate (ORR), percentage of patients with grade 3 or higher adverse event (AE), discontinuation due to AE, and rates of AEs of clinical interest. We used a Bayesian hierarchical random-effects models for mixed multiple treatment comparisons to estimate the relative treatment effect of each intervention compared with a common comparator. Results: Our search yielded 12 clinical trials including 15 unique 1L regimens (Fig 1). PFS and ORR of common comparators were consistent across trials except 24-month PFS for chlorambucil/obinutuzumab (CO) which ranged from 31%-64% likely due to variable duration of chlorambucil and variable inclusion of patients with del(17p). Compared to CO, only acalabrutinib/obinutuzumab (AO) showed statistically significant improvement in 24-month PFS with hazard ratio (HR) 0.13 and 95% confidence interval (CI) 0.017-0.97 (Fig 1). In general, targeted therapies trended towards longer PFS compared to chemotherapy-based regimens, though there is insufficient power to demonstrate statistical significance. We found no statistically significant differences in 24-month PFS, 48-month PFS, or ORR between targeted therapies. Regarding toxicity, no statistically significant differences in proportion of patients experiencing grade 3 or higher AE were found across regimens, though single agent acalabrutinib and zanubrutinib trended toward less toxicity than CO with risk ratio (RR) 0.71, 95% CI 0.45-1.1 and RR 0.66, 95% CI 0.30-1.5, respectively. No statistically significant differences in discontinuation rates were found, though IV trended towards higher discontinuation rate than CO (RR 6.1, 95% CI 0.71-74). There were no statistically significant differences in rates of atrial fibrillation, infection, anemia, or neutropenia. However, grade 3 or higher thrombocytopenia was significantly lower with zanubrutinib than CO (RR 0.069, 95% CI 0.0048-0.92). Conclusions: Using NMA, we demonstrate that PFS is improved from the pre-targeted therapy standard of care by AO, but, amongst targeted therapies, no significant differences in efficacy were identified. Our results differ from previously published NMAs which have shown superior PFS with AO compared to other targeted therapies, likely due to inclusion of additional trials of common comparators (Foa et al, CLL5) as well as newer trials assessing IV and zanubrutinib (GLOW, SEQUOIA cohort 1) in this analysis. All four trials add heterogeneity to common comparator outcomes, resulting in widened confidence intervals and loss of statistical significance. This is the first assessment, to our knowledge, of relative rates of specific AEs, and we found that zanubrutinib showed lower rates of thrombocytopenia than pre-targeted therapy standard of care. Establishing the absence of significant difference in efficacy of frontline targeted therapies in CLL allows the clinician and patient to select therapy based on other factors, namely planned duration, toxicity profile, medication interactions, and cost. Figure 1. 24-month PFS Network and Forest Plot 1Chl = Chlorambucil; Acal = Acalabrutinib; Acal/Obin = Acalabrutinib/Obinutuzumab; BR = Bendamustine/Rituximab; Chl/Ofa = Chlorambucil/Ofatumumab; Chl/Ritux = Chlorambucil/Rituximab; Chl/Ritux + Mtn = Chlorambucil/Rituximab + maintenance Rituximab; Flu = Fludarabine; Ibr = Ibrutinib; Ibr/Obin = Ibrutinib/Obinutuzumab; Ibr/Ritux = Ibrutinib/Rituximab; Ibr/Ven = Ibrutinib/Venetoclax; Ven/Obin = Venetoclax/Obinutuzumab; Zan = Zanubrutinib Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

INNV-09. IMPACT OF MOLECULAR MARKERS ON TREATMENT OUTCOME OF GLIOBLASTOMA PATIENTS TREATED WITH CONCURRENT TUMOR-TREATING FIELDS (TTF) AND CHEMORADIATION: SECONDARY ANALYSIS OF SPARE TRIAL

Abstract OBJECTIVES SPARE trial (Scalp-sparing radiation with concurrent temozolomide and tumor treating fields; NCT03477110) is a single-arm pilot study that evaluated the safety and feasibility of concurrent TTF with chemoradiation for adult patients with newly diagnosed GBM. The current study is a secondary analysis evaluating the impact of molecular markers (PTEN, TP53, EGFR, and TERT) on overall survival (OS) and progression-free survival (PFS) of the patients in the trial. METHODS Molecular markers of histologically-confirmed, IDH-wildtype GBM patients age ≥ 18 years old with a KPS ≥ 60 who received concurrent chemoradiation and TTF followed by maintenance TMZ + TTF were evaluated. Molecular profile was evaluated with next-generation sequencing. Impact of mutations in PTEN, TP53, EGFR, and TERT on OS and PFS was evaluated using a multivariable backward model. RESULTS A total of 30 patients were enrolled in the SPARE trial, and 1 patient with IDH-mutant was excluded from the current analysis. All patients underwent concurrent TTF and chemoradiation. The median age is 58 and KPS was 90. 9 patients had methylated MGMT promotor. 14 patients were found to have PTEN mutation, 9 patients with EGFR, 7 with TP53 mutation, and 23 patients with TERT mutated. MGMT methylation remained statistically significant for an increased OS (p=0.032; HR 7.18). TERT mutation had a statistically significant improvement in PFS (P=0.003) and OS (p=0.012). However, neither EGFR, TP53, nor PTEN showed any association of PFS or OS for patients who received concurrent TTF and CRT. CONCLUSIONS In this secondary analysis, patients with MGMT methylation showed better PFS and OS as expected. Neither EGRF, TP53, or PTEN mutation showed any association with PFS or OS. Patients with TERT mutant showed improved OS of patients treated with concurrent TTF with chemoradiation. A TERT mutation may be a new molecular biomarker in the described treatment approach.

CTNI-47. TUMOR TREATING FIELDS COMBINE WITH TEMOZOLOMIDE FOR NEWLY DIAGNOSED GLIOBLASTOMA: A RETROSPECTIVE ANALYSIS OF CHINESE PATIENTS

Abstract BACKGROUND TTFields plus Temozolomide (TTFields/TMZ) extended survival versus TMZ alone in newly diagnosed glioblastoma (GBM) patients in the EF-14 trial. We report a retrospective analysis of Chinese newly diagnosed GBM patients who received TTFields combine with TMZ treatment and traditional TMZ monotherapy from May 2019 to May 2021 in Shanghai Hua Shan hospital.METHOD: Overall survival (OS) and progression-free survival (PFS) curves were constructed using the Kaplan-Meier method. A Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) based on propensity score was used to assess the effect of TTFields and account for confounding factors. RESULT: In the preliminary analysis, the PFS in the TTFields/TMZ arm was 16 months (95% CI:9.6–24.6) versus 11 (95% CI: 9–12) with TMZ alone (p ＜0.05). Median overall survival was 21.8 months (95% CI 17.4-NA) with TTFields/TMZ versus 15 months (95% CI 13–18; HR 0.43, p ＜0.01) with TMZ alone. In the Multivariate analysis, Surgery type, STUPP scheme, IDH status, and TTFields use were identified as favorable prognostic factors. After PSM adjustment, the groups were similar, except that MGMT promoter methylation remained more in the TMZ group (12 v 32; P = 0.011). Upon IPTW Survival analysis, TTFields was associated with a significantly lower risk of death (hazard ratio [HR], 0.19 in OS (95% CI 0.09–0.41) and progression (HR, 0.35 (95% CI 0.14–0.91) compared with TMZ alone. CONCLUSION In the analysis of our single center of patients with glioblastoma, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the outcome of EF-14.

Diffusion-weighted MRI to determine response and long-term clinical outcomes in muscle-invasive bladder cancer following neoadjuvant chemotherapy

This study aims to determine local treatment response and long-term survival outcomes in patients with localised muscle-invasive bladder cancer (MIBC) patients receiving neoadjuvant chemotherapy (NAC) using diffusion-weighted MRI (DWI) and apparent diffusion coefficient (ADC) analysis. Patients with T2-T4aN0-3M0 bladder cancer suitable for NAC were recruited prospectively. DWI was performed prior to NAC and was repeated following NAC completion. Conventional response assessment was performed with cystoscopy and tumour site biopsy. Response was dichotomised into response (<T2) or poor response (≥T2). Patients proceeded to either radical cystectomy or chemo-radiotherapy as standard of care. Tumour ADC values were calculated for all b-values (ADCall) and high b-values (ADCb100). Mean ADC, percentiles, skew, kurtosis, and their change (ΔADC and %ΔADC) were determined. Threshold predictive of response with highest specificity was ascertained using receiver operating characteristic (ROC) analysis. Median overall survival (OS), bladder-cancer-specific survival (bCSS), progression-free survival (PFS), and time to cystectomy were estimated using Kaplan-Meier method. Significant area under the curve (AUC) cut points were used to determine relationship with long-term endpoints and were compared using log-rank test. Forty-eight patients (96 DWI) were evaluated. NAC response was associated with significant increase in mean ΔADC and %ΔADC compared to poor response (ΔADCall 0.32×10-3 versus 0.11×10-3 mm2/s; p=0.009, and %ΔADCall 21.70% versus 8.23%; p=0.013). Highest specificity predicting response was seen at 75th percentile ADC (AUC, 0.8; p=0.01). Sensitivity, specificity, positive predictive power, and negative predictive power of %ΔADCb100 75th percentile was 73.7%, 90.0%, 96.6%, and 52.9%, respectively. %ΔADCb100 75th percentile >15.5% was associated with significant improvement in OS (HR, 0.40; 95% CI, 0.19-0.86; p=0.0179), bCSS (HR, 0.26; 95% CI, 0.08-0.82; p=0.0214), PFS (HR, 0.16; 95% CI, 0.05-0.48; p=0.0012), and time to cystectomy (HR, 0.19; 95% CI, 0.07-0.47; p=0.0004). Quantitative ADC analysis can successfully identify NAC response and improved long-term clinical outcomes. Multi-centre validation to assess reproducibility and repeatability is required before testing within clinical trials to inform MIBC treatment decision making. We successfully demonstrated that measured change in DWI can successfully identify NAC response and improved long-term survival outcomes.

Longitudinal Survival Outcomes in Allogeneic Stem Cell Transplantation: An Institutional Experience.

We analyzed data from 1943 consecutive patients who received allo-SCT. Patients were divided into groups (gps) based on the year (yr) of transplant. Primary endpoints were overall survival (OS), progression free survival (PFS), and GVHD-free relapse-free survival (GRFS). Secondary endpoints were the cumulative incidences of grade II-IV and grade III-IV acute GVHD (aGVHD), chronic GVHD (cGVHD), and non-relapse mortality (NRM). Our study found statistically significant improvements in OS, PFS, and GRFS. Five-year PFS among the groups increased from 24% to 48% over the years. Five-year OS increased from 25% to 53%. Five-year GRFS significantly increased from 6% to 14%, but remained relatively unchanged from 2004 to 2018. Cumulative incidences of grade II-IV aGVHD increased since 2009 (p &lt; 0.001). However, cumulative incidence of NRM decreased since 2004 (p &lt; 0.001). Our data show improved OS, PFS, and GRFS post allo-SCT over decades. This may be attributed to advances in supportive care and treatments focused on mitigation of GVHD and relapse.

Recruiting Immunity for the Fight against Colorectal Cancer: Current Status and Challenges.

Cancer immunotherapies have changed the landscape of cancer management and improved the standard treatment protocols used in multiple tumors. This has led to significant improvements in progression-free survival and overall survival rates. In this review article, we provide an insight into the major immunotherapeutic methods that are currently under investigation for colorectal cancer (CRC) and their clinical implementations. We emphasize therapies that are based on monoclonal antibodies (mAbs) and adoptive cell therapy, their mechanisms of action, their advantages, and their potential in combination therapy. We also highlight the clinical trials that have demonstrated both the therapeutic efficacy and the toxicities associated with each method. In addition, we summarize emerging targets that are now being evaluated as potential interventions for CRC. Finally, we discuss current challenges and future direction for the cancer immunotherapy field.

Pre-therapeutic evaluation and practical management of cardiovascular and renal toxicities in patients with metastatic radioiodine-refractory thyroid cancer treated with lenvatinib

ABSTRACT Introduction Multi-receptor tyrosine kinase inhibitors with anti-angiogenic activity, particularly lenvatinib, have become the standard treatment for radioiodine-refractory metastatic differentiated thyroid cancer but are associated with a high incidence of toxicity. Although patients treated with lenvatinib have been shown to have a significant improvement in progression-free survival, lenvatinib-associated toxicity may result in dose reductions, dose interruptions or even complete lenvatinib withdrawal, compromising anti-tumor efficacy. Areas covered The article covers the main cardiological and renal toxicities of lenvatinib, including hypertension, prolonged QT interval, heart failure, arterial and venous thromboembolic events, proteinuria and renal failure, and proposes appropriate management of these events during lenvatinib therapy. We performed a literature review of cardiovascular and renal toxicities of Lenvatinib in radioiodine-refractory differentiated thyroid cancer. We discussed prophylactic and therapeutic management for each toxicity based on literature and clinical expertise. Expert opinion Specific pre-therapeutic evaluation and close monitoring of patients treated with lenvatinib is necessary to prevent and detect cardiovascular and/or renal toxicities early, and to propose appropriate management. Oncologists who treat patients with lenvatinib should know how to monitor and treat these adverse events, and when to ask for the advice of a specialist (cardiologist or nephrologist).

Efficacy and safety of vorolanib plus everolimus in metastatic renal cell carcinoma: A three-arm, randomised, double-blind, multicentre phase III study (CONCEPT)

BackgroundVorolanib is a highly potent tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor. This three-arm, randomised, registered study aimed to assess the combination of vorolanib and everolimus or vorolanib alone versus a control arm of everolimus as second-line treatment in patients with metastatic renal cell carcinoma (RCC). Patients and methodsPatients with advanced or metastatic RCC who had received one prior VEGFR-TKI were randomised (1:1:1) to receive the combination of vorolanib and everolimus or either monotherapy. Patients with brain metastases were excluded. The primary end-point was progression-free survival (PFS) assessed by the independent review committee per Response Evaluation Criteria in Solid Tumours v1.1. ResultsBetween 10th March 2017 and 30th May 2019, 399 patients (133 in each group) were enrolled. By the cutoff date (30th April 2020), a significant improvement in PFS was detected in the combination group compared with the everolimus group (10.0 versus 6.4 months; hazard ratio, 0.70; P = 0.0171). PFS was similar between the vorolanib group and the everolimus group (median: 6.4 versus 6.4 months; hazard ratio, 0.94; P = 0.6856). A significantly higher objective response rate was observed in the combination group than in the everolimus group (24.8% versus 8.3%; P = 0.0003), whereas there was no significant difference between the vorolanib group and the everolimus group (10.5% versus 8.3%; P = 0.5278). The overall survival data were immature. A total of 96 (72.2%), 52 (39.1%) and 71 (53.4%) grade 3 or higher treatment-related adverse events occurred in the combination group, vorolanib group and everolimus group, respectively. ConclusionsThe addition of vorolanib to everolimus as 2nd-line treatment for patients with advanced or metastatic RCC who have experienced cancer progression after VEGFR-TKI therapy provided a better objective response rate and PFS than everolimus alone with a manageable safety profile. Trial registrationClinicalTrials.gov, NCT03095040; Chinadrugtrials, CTR20160987.

Comparison of surgery with or without adjuvant radiotherapy in treating central neurocytoma: a single-center retrospective real-world study.

To investigate the efficacy and safety of adjuvant radiotherapy (RT) in patients with central neurocytoma (CN). The study included 68 patients with CN retrospectively, wasfurther divided into surgery + RT group (31 patients) and surgery alone group (37 patients). Progression-free survival (PFS), overall survival (OS), and adverse reactions (AEs) were compared between the two groups. The median follow-up duration was 82.2 (interquartile range, 64.7-104.5) months. Patients in the surgery + RT group tended to have longer PFS than those in the surgery alone group (5-year PFS rate: 92.7% vs. 86.3%; P = 0.074). There was no significant difference in OS between the two groups (5-year OS rate: 96.8% vs. 94.3%; P = 0.639). Subgroup analysis revealed a significant improvement in PFS in patients receiving RT after surgery in patients who underwent subtotal resection (STR) (P = 0.045). In the overall population, univariate multivariate analysis revealed that gross total resection (GTR) (P = 0.002), tumor location in the unilateral ventricle (P = 0.008), and MIB-1 (Ki-67)labeling index (LI) < 5% (P = 0.009) were favorable independent prognostic factors for PFS. Whereas tumor location in the unilateral ventricle (P = 0.043) was a favorable independent prognostic factor for OS. Moreover, RT patients experienced AEs (Grade 1-2, well-tolerated). Adjuvant RT in the treatment of CNs showed satisfactory safety, and postoperative RT could improve PFS in STR patients. Furthermore, GTR, tumor development in the unilateral ventricle, and MIB-1LI < 5% were found to be favorable factors affecting the prognosis of CNs.