Median Overall Survival Duration Research Articles

Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial.

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg-1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6-62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79-19.12), 8.18 months (95% CI = 6.67-10.48) and 17.48 months (95% CI = 12.35-26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67-not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63-31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027.

Belantamab mafodotin in triple‐refractory multiple myeloma patients: A retro‐prospective observational study in Italy

AbstractBelantamab mafodotin is the first‐in‐class antibody‐drug conjugates targeting B‐cell maturation antigen to have demonstrated effectiveness in triple‐class refractory multiple myeloma (TCR‐MM) patients. We performed a retrospective study including 78 TCR patients, with at least four prior lines of therapy (LOTs), who received belantamab mafodotin within named patient program and expanded access program in Italy between 2020 and 2022. Median age was 65 years (range 42–86 years), ECOG performance status was ≥1 in 45% of patients. Overall, a clinical benefit was obtained in 36 out of 74 evaluable patients (49%), with 43%, 28%, and 13.5% achieving at least partial response, very good partial response, and complete response, respectively. After a median follow‐up of 12 months (range 6–21 months), median duration of response, progression‐free survival (PFS), and overall survival (OS) were 14, 5.5, and 12 months, respectively. Age &gt;70 years, good performance status and response were associated with longer PFS and OS. Keratopathy occurred in 58% of patients (G3 2.5%), corneal symptoms in 32% (G3 1.2%) and a reduction in visual acuity in 14%. Grade 3 thrombocytopenia occurred in 9% of patients. Only 3% of patients discontinued belantamab mafodotin because of side effects. This real‐life study demonstrated significant and durable responses of belantamab in TCR‐MM patients with four prior LOTs, otherwise ineligible for novel immunotherapies.

High pre-chemoradiotherapy pan-immune-inflammation value levels predict worse outcomes in patients with stage IIIB/C non-small-cell lung cancer

Background and objectivesWe explored the prognostic usefulness of the pan-immune-inflammation value (PIV) in patients with stage IIIB/C non-small-cell lung cancer (NSCLC) who underwent concurrent chemoradiotherapy (CCRT).Methods and patientsFor all patients, the PIV was calculated using platelet (P), monocyte (M), neutrophil (N), and lymphocyte (L) measures obtained on the first day of CCRT: PIV = P × M × N ÷ L. Using receiver operating characteristic (ROC) curve analysis, we searched for the existence of an ideal cutoff that may partition patients into two groups with unique progression-free- (PFS) and overall survival (OS) results. The primary endpoint of this retrospective cohort research was to determine whether there were any significant relationships between pretreatment PIV measures and post-CCRT OS outcomes.ResultsThe present research included a total of 807 stage IIIB/C NSCLC patients. According to ROC curve analysis, the ideal PIV cutoff was 516 [area under the curve (AUC): 67.7%; sensitivity: 66.4%; specificity: 66.1%], which divided the whole cohort into two: low PIV (L-PIV: PIV < 516; N = 436) and high PIV (H-PIV: PIV ≥ 516; N = 371). The comparisons between the PIV groups indicated that either the median PFS (9.2 vs. 13.4 months; P < 0.001) or OS (16.7 vs. 32.7 months; P < 0.001) durations in the H-PIV group were substantially inferior to their L-PIV counterpart. Apart from the H-PIV (P < 0.001), the N3 nodal stage (P = 0.006), IIIC disease stage (P < 0.001), and receiving only one cycle of concurrent chemotherapy (P = 0.005) were also determined to be significant predictors of poor PFS (P < 0.05, for each) and OS (P < 0.05, for each) outcomes in univariate analysis. The multivariate analysis findings revealed that all four variables had independent negative impacts on PFS (P < 0.05, for each) and OS (P < 0.05, for each).ConclusionsThe findings of this hypothesis-generating retrospective analysis claimed that the novel PIV was an independent and steadfast predictor of PFS and OS in stage IIIB/C NSCLC patients.

Management and long-term clinical outcomes of patients with stage IVA cervical cancer with bladder involvement

ObjectiveTo describe the long-term outcomes of patients with stage IVA cervical cancer, a rare and deadly disease for which long-term toxicity data are scarce, to guide clinician counseling and survivorship support. MethodsIn a retrospective review of a prospectively maintained database, we identified 76 patients with stage IVA cervical cancer with biopsy- or MRI-proven bladder mucosal involvement who received definitive radiotherapy (external beam radiotherapy [EBRT] alone or EBRT plus brachytherapy) with or without chemotherapy at our institution between 2000 and 2020. We used Kaplan-Meier modeling to estimate recurrence-free survival (RFS) and overall survival (OS) and used proportional hazard modeling to identify clinical variables associated with recurrence or survival. We performed actuarial competing risk modeling for severe late toxicity (grades 3 to 5, occurring >6 months of follow-up) and vesicovaginal fistulae (VVF), censoring for pelvic recurrence and death, and made comparisons between potential predictors using Gray's test and binary logistic regression. ResultsThe median follow-up time was 76 months (interquartile range 58–91). The median OS duration was 35 months (range, 18-not reached), and the 2- and 5-year OS rates were 53.6% and 40.9%, respectively. OS and RFS did not differ significantly between patients who received EBRT alone (N = 18) or EBRT plus brachytherapy (N = 49). Current smoking was a strong predictor of severe late toxicity, whose incidence was 14% at 2 years and 17% at 10 years. The VVF incidence was 24% at 2 years and 32% at 10 years. ConclusionPatients with stage IVA cervical cancer, even those who receive EBRT alone, can have long-term survival. These patients should be followed closely for late radiation-related toxicity.

Multicenter randomized controlled trial of neoadjuvant chemoradiotherapy alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a challenging target for immunotherapy because it has an immunosuppressive tumor microenvironment. Neoadjuvant chemoradiotherapy can increase tumor-infiltrating lymphocyte (TIL) density, which may predict overall survival...

Efficacy and Safety of Elranatamab in Black Patients with Relapsed/Refractory Multiple Myeloma (RRMM): A Subgroup Analysis of the Magnetismm Studies

INTRODUCTION Multiple myeloma disproportionately impacts ethnic and racial minority groups, affecting both incidence and outcome. There is limited evidence-based data for clinical decision making for minority populations, including Black patients (Habr and Corsaro, Hematol Oncol 2022). Elranatamab is a B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the phase 2 registrational trial MagnetisMM-3, elranatamab demonstrated clinical efficacy in BCMA-naïve and BCMA-exposed patient populations. Here, we report the efficacy and safety of elranatamab in a pooled analysis of Black or African American patients with RRMM across 3 studies in the MagnetisMM program, including MagnetisMM-1 (MM-1; NCT03269136), MagnetisMM-3 (MM-3; NCT04649359), and MagnetisMM-9 (MM-9; NCT05014412). METHODS Eligible patients included in this pooled analysis had previously received at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody, and were either naïve or exposed to prior BCMA-directed therapy (antibody-drug conjugate [ADC] and/or CAR T-cells). All patients received subcutaneous elranatamab at the effective doses of 215-1000 µg/kg or fixed dose equivalent of 76 mg (MM-1) or 76 mg once-weekly (MM-3 and MM-9). Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. Evaluation of overall response rate (ORR) was assessed per IMWG criteria. Adverse events (AEs) and laboratory abnormalities were graded by National Cancer Institute Common Terminology Criteria for AEs v4.03 (MM-1) or v5.0 (MM-3 and MM-9). American Society for Transplantation and Cellular Therapy criteria (Lee DW, et al. Biol Blood Marrow Transplant 2019) were used for grading cytokine release syndrome (CRS) and immune effect cell-associated neurotoxicity syndrome (ICANS). RESULTS Of 24 Black or African American patients in the pooled analysis who received elranatamab, the median age was 61.5 years (36-76), 75.0% had R-ISS Stage I or II disease, 79.2% had prior stem cell transplant, and 91.7% patients had an Eastern Cooperative Oncology performance status of 0 or 1. Patients had a median of 6 prior lines of therapy (range, 2-14), with 91.7% and 45.8% having triple-class and penta-drug refractory disease, respectively. Seven patients (29.2%) received prior BCMA-directed therapy as either an antibody-drug conjugate (ADC; n=5), CAR-T (n=4), or both (n=2). After a median follow-up of 13.3 months, the median duration of treatment was 9.0 months; 6 (25%) patients were still on treatment. The most common reasons for treatment discontinuation were progressive disease (41.7%), AEs (12.5%), and death (12.5%). The ORR was 58.3%, with 41.7% of patients achieving complete responses (CR) or better (Table). The median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were 18.4, 14.4, and 21.2 months, respectively. Common treatment-emergent AEs (TEAEs) included CRS, anemia, and neutropenia (Table). Infections were reported in 15 patients (any grade, 62.5%; grade 3/4, 20.8%). Two cases of ICANS (both grade 2) were reported. One patient died due to disease progression (metastases to meninges), and four patients died due to a TEAE other than disease progression: 1 patient each due to COVID-19, septic shock, sudden death, and pulmonary embolism. CONCLUSIONS Elranatamab demonstrated clinical activity and a manageable safety profile in Black or African American patients with RRMM, supporting the use of elranatamab in this subgroup of patients. Efficacy and safety results are comparable to those observed for the overall population of patients treated with elranatamab in the phase 2 MagnestisMM-3 trial. No new safety signals were observed.

Real-World Analysis of Teclistamab in 115 RRMM Patients from Germany

Background Bispecific antibodies and CAR-T cells are currently changing the treatment landscape of relapsed and refractory multiple myeloma (RRMM), having shown high response rates and durable remissions of more than a year in clinical trials. However, some discrepancies to these results have been observed lately, with lower median progression free survival (PFS) and overall survival (OS) in the real-world setting for idecabtagene vicleucel (ide-cel), possibly related to strict entry criteria of the study and known general benefits for patients participating in clinical trials regardless of study arm allocation. Whether this also holds true for Teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody approved for treatment of RRMM in 2022 in several countries, has yet to be determined. Therefore, we thought to assess Teclistamab efficacy and tolerability in the real-world setting. Methods Data of 115 patients with RRMM treated with Teclistamab at 18 different German centers from July 2022 to July 2023 were retrospectively collected and analyzed. The patients had received at least one full treatment dose of Teclistamab. Responses were evaluated in accordance with the IMWG response criteria; in addition, near complete response was defined as serological complete remission lacking bone marrow assessment, as this was not always part of clinical routine. In non-secretory disease, response evaluation was based on radiological criteria. Kaplan-Meier methods were applied for time-to-event-analyses. For comparison of survival among groups, the log-rank test and Cox regression analysis were used. For comparison of response rates among groups, the Chi square test was applied. Results The included 115 patients (49 female, 66 male with a median age of 66.0 years) had a median history of MM diagnosis of 6.5 years and were heavily pretreated with a median of 6 (range 3-14) prior lines of therapy. The majority of patients had triple-class (91.3%) or even penta-drug (58.3%) refractory disease. 35.6% (41/115) had received BCMA-directed pretreatment, among them 20 with ide-cel, 21 with belantamab mafodotin and single patients with both or a BCMA-directed study medication. Cytogenetic high-risk features defined as del(17p), t(4;14) and/or t(14;16) and extramedullary disease (EMD) were present in 38.0% and 37.2% of patients, respectively. Around one third of patients had high disease burden with bone marrow infiltration ≥60% (37.0%) or ISS 3 (35.2%) in the latest assessment before initiation of Teclistamab. Overall, a substantial proportion of 40.9% of the treated patients would not have met selected inclusion criteria of the MAJESTEC-1 trial like measurable disease, stable hematopoiesis and kidney function. With median times to response and best response of 4.3 weeks and 8.0 weeks, we observed an ORR, defined as partial remission or better, of 56.8%. 20.9% of all patients reached a near complete or complete response. With a median follow-up of 3.9 months, median PFS was 8.7 months. Median duration of response and median OS were not reached. In the group of patients with BCMA-directed pretreatment, the ORR of belantamab-pretreated patients (70%) was comparable to that in anti-BCMA naïve patients (60.0%), whereas ide-cel pretreated patients showed a significantly lower ORR of 27.8%. Interestingly, PFS did not differ significantly between ide-cel pretreated and ide-cel naïve patients. In further subgroup analyses, the presence of EMD and an ISS of 3 were associated with inferior ORR and PFS in univariable and multivariable analysis. Safety was similar to the experience in MAJESTEC-1. 60.0% of patients developed CRS and 6.9% neurotoxicity with grade 3 or 4 events in 1.7% and 0.9% of patients, respectively. Tocilizumab was administered in 25.2% and dexamethasone in 15.7% of patients. Infections occurred in 49.6% of patients, nearly half of them requiring hospitalization. 53.9% experienced grade 3 or 4 cytopenia according to CTCAE during treatment. Conclusions With an ORR of 56.8% in all patients and 60.0% in anti-BCMA naive patients, Teclistamab showed a similar ORR in the real-world setting to that observed in the MAJESTEC-1 trial. PFS was slightly lower, but our patient collective comprised higher proportions of patients with high risk disease, extramedullary disease, high disease burden, hematopoietic or renal impairment.

Retrospective Analysis of Four Frailty Assessment Tools in Elderly Patients with Multiple Myeloma

INRTODUCTION : The International Myeloma Working Group (IMWG) developed the frailty index (IMWG-FI) to predict the toxicity and mortality risk faced by elderly patients with multiple myeloma. However, due to the time-consuming nature and subjectivity of IMWG-FI, alternative frailty assessment tools have been developed to reduce subjectivity and enhance the ability to identify frailty. O BJECTIVE (S) To assess the consistency of various frailty assessment tools in elderly patients with multiple myeloma and their predictive efficacy for patients survival. M ETHOD (S) We systematically assessed 84 newly diagnosed multiple myeloma patients aged≥60 years old using various frailty assessment tools, including the IMWG frailty index (IMWG-FI), Mayo frailty score, simplified IMWG frailty index（IFM）, and British Myeloma Research Alliance Risk (MRP) score. We compared progression-free survival (PFS) and overall survival (OS) outcomes based on these different assessment tools. For the purpose of analysis, we combined patients categorized as Fit or Intermediate Fit into a single group called Non-Frail. RESULTS (S) The median age of the included patients was 68 years, ranging from 60 to 84 years. Among them, 59.5% were male. Additionally, 53.8% had an ECOG score of ≥2 and 26.9% had a CCI score of ≥2. Patients who chose the regimens based on ixazomib, bortezomib, and thalidomide were 11.2%, 70.7%, and 3.3%, respectively, while 7.8% of patients refused chemotherapy. The incidence of frailty in this cohort was as follows: 53.6% according to the IMWG-FI, 23.8% based on the Mayo frailty score, 46.4% using the MRP frailty score, and 67.85% according to the simplified IMWG frailty index. The consistency among the four frailty assessment tools was low, with a total of 64 patients (76.2%) identified as frail by at least one tool. Among them, 48 patients (75.0%) were identified as frail by at least two tools, while only 14 patients (21.9%) were classified as frail by all four tools. Among the cohort of 73 patients eligible for OS and PFS analysis, utilization of the IMWG-FI to evaluate frailty status revealed that the non-frail and frail groups exhibited median OS durations of undisclosed levels and 15.5 months, respectively ( P=0.01). In terms of PFS, the corresponding median durations were 42.5 months and 10.0 months, respectively ( P=0.011). When employing the Mayo frailty score, the non-frail and frail groups demonstrated median OS durations of 26.0 months and 7.0 months, respectively ( P=0.004), alongside median PFS durations of 42.5 months and 7.0 months, respectively ( P=0.024). Application of the MRP score to assess frailty resulted in non-frail and frail groups achieving undisclosed levels and a median OS of 15.0 months, respectively ( P&amp;lt;0.001). Their corresponding median PFS durations were 42.5 months and 9.0 months, respectively ( P&amp;lt;0.001). Additionally, the utilization of the simplified IMWG frailty index for frailty assessment rendered non-frail and frail groups achieving undisclosed levels and a median OS of 19.0 months, respectively ( P=0.225). Regarding the median PFS durations, they reached undisclosed levels and 15.0 months for the non-frail and frail groups, respectively ( P=0.495). CONCLUSION (S) The results of the four frailty assessment tools in this cohort vary significantly. The MRP score and IMWG frailty index demonstrate higher consistency and better prognostic stratification efficiency compared to the Mayo score and simplified IMWG frailty index. Therefore, combining the MRP score with the IMWG frailty index can effectively enhance the recognition ability for newly diagnosed elderly patients with frail multiple myeloma.

The Prognostic Value of the Novel Global Immune-Nutrition-Inflammation Index (GINI) in Stage IIIC Non-Small Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy.

We sought to determine the prognostic value of the newly developed Global Immune-Nutrition-Inflammation Index (GINI) in patients with stage IIIC non-small cell lung cancer (NSCLC) who underwent definitive concurrent chemoradiotherapy (CCRT). This study was conducted on a cohort of 802 newly diagnosed stage IIIC NSCLC patients who underwent CCRT. The novel GINI created first here was defined as follows: GINI = [C-reactive protein × Platelets × Monocytes × Neutrophils] ÷ [Albumin × Lymphocytes]. The receiver operating characteristic (ROC) curve analysis was used to determine the optimal pre-CCRT GINI cut-off value that substantially interacts with the locoregional progression-free (LRPFS), progression-free (PFS), and overall survival (OS). The optimal pre-CCRT GINI cutoff was 1562 (AUC: 76.1%; sensitivity: 72.4%; specificity: 68.2%; Youden index: 0.406). Patients presenting with a GINI ≥ 1562 had substantially shorter median LRPFS (13.3 vs. 18.4 months; p < 0.001), PFS (10.2 vs. 14.3 months; p < 0.001), and OS (19.1 vs. 37.8 months; p < 0.001) durations than those with a GINI < 1562. Results of the multivariate analysis revealed that the pre-CCRT GINI ≥ 1562 (vs. <1562), T4 tumor (vs. T3), and receiving only 1 cycle of concurrent chemotherapy (vs. 2-3 cycles) were the factors independently associated with poorer LRPS (p < 0.05 for each), PFS (p < 0.05 for each), and OS (p < 0.05 for each). The newly developed GINI index efficiently divided the stage IIIC NSCLSC patients into two subgroups with substantially different median and long-term survival outcomes.

Efficacy and Tolerability of Enfortumab Vedotin for Metastatic Urothelial Carcinoma: Early Experience in the Real World.

This study retrospectively investigated the impact of enfortumab vedotin (EV) monotherapy on the oncological outcome, safety profile, and health-related quality of life (HRQoL) in patients with metastatic urothelial carcinoma. We assessed 26 consecutive patients who had received EV monotherapy after failure of platinum-based chemotherapy and immune checkpoint blockade therapy at our single institution from December 2021 to January 2023. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and EORTC QLQ-C30 as an HRQoL instrument were evaluated. The ORR and DCR were 57.7% and 80.8%, respectively. EV was effective regardless of the patient and tumor characteristics, including the efficacy of previous systemic therapy, performance status, number of Bellmunt risk factors, and presence of variant histology. With a median follow-up time of 7.5 months, the median durations of PFS and OS were 5.4 months and 10.3 months, respectively. Grade ≥3 AEs included neutropenia (15.4%), fatigue (7.7%), appetite loss (7.7%), rash (3.8%), febrile neutropenia (3.8%), hyperglycemia (3.8%), and interstitial pneumonia (3.8%). AEs resulting in withdrawal of EV, interruption of EV, and dose reduction occurred in two (7.7%), nine (34.6%), and 13 patients (50.0%), respectively. The EORTC QLQ-C30 scores from baseline to post-EV introduction remained stable. EV monotherapy demonstrated promising anti-tumor activity and tolerability in patients with metastatic urothelial carcinoma.

Idecabtagene vicleucel for relapsed and refractory multiple myeloma: post hoc 18-month follow-up of a phase 1 trial

Idecabtagene vicleucel (ide-cel) is a B-cell-maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy. We performed a post hoc analysis of a single-arm phase 1 multicenter study in relapsed/refractory multiple myeloma (CRB-401) (n = 62; median follow-up, 18.1 months). The primary endpoint was safety outcomes, and secondary endpoints included overall response rate (ORR), complete response (CR) and very good partial response (VGPR). The study met its primary endpoint with low rates of grade 3/grade 4 cytokine release syndrome (6.5%) and neurotoxicity (1.6%). ORR was 75.8%; 64.5% achieved VGPR or better and 38.7% achieved CR or stringent CR. Among exploratory endpoints, median duration of response, progression-free survival (PFS) and overall survival were 10.3, 8.8 and 34.2 months, respectively, and ide-cel expansion in blood and bone marrow correlated with clinical efficacy and postinfusion reduction of soluble BCMA. Patients with PFS ≥ 18 months had more naive and less exhausted T cells in apheresis material and improved functional T cell phenotype in the drug product compared with those with less durable responses. These results confirm ide-cel safety, tolerability and efficacy and describe T cell qualities that correlate with durable response. Clinicaltrials.gov identifier : NCT02658929.

Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results

Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing. Results from cohort A, which enrolled patients without prior BCMA-directed therapy (n = 123) are reported. The primary endpoint of confirmed objective response rate (ORR) by blinded independent central review was met with an ORR of 61.0% (75/123); 35.0% ≥complete response. Fifty responders switched to biweekly dosing, and 40 (80.0%) improved or maintained their response for ≥6 months. With a median follow-up of 14.7 months, median duration of response, progression-free survival and overall survival (secondary endpoints) have not been reached. Fifteen-month rates were 71.5%, 50.9% and 56.7%, respectively. Common adverse events (any grade; grade 3–4) included infections (69.9%, 39.8%), cytokine release syndrome (57.7%, 0%), anemia (48.8%, 37.4%), and neutropenia (48.8%, 48.8%). With biweekly dosing, grade 3–4 adverse events decreased from 58.6% to 46.6%. Elranatamab induced deep and durable responses with a manageable safety profile. Switching to biweekly dosing may improve long-term safety without compromising efficacy. ClinicalTrials.gov identifier: NCT04649359.

Exploring causes and consequences of early discontinuation of durvalumab after chemoradiotherapy for non-small cell lung cancer.

For most locally advanced non-small cell lung cancer (LA-NSCLC) patients who complete definitive chemoradiotherapy (CRT) and do not experience disease progression, one year of adjuvant durvalumab is recommended. Here, we explore causes and consequences of early durvalumab discontinuation. We reviewed patients treated for LA-NSCLC with definitive CRT who began adjuvant durvalumab between 2017 and 2021. Duration of durvalumab receipt and causes for early discontinuation were tabulated. Logistic regression models were utilized to evaluate predictors of early durvalumab discontinuation. Landmark analyses were performed to explore associations between early durvalumab discontinuation and clinical outcomes (progression-free survival (PFS), overall survival (OS)). Fifty-nine patients were included. Forty-one patients (69%) discontinued durvalumab early, most commonly for disease progression (n=14) or lung toxicity (n=10). Multivariable analysis revealed mean heart radiotherapy dose (MHD) was associated with risk of durvalumab discontinuation from progression (HR=2.34 per 10Gy, p=0.052), and there was a trend suggesting an association between MHD and risk of durvalumab discontinuation from lung toxicity (HR=2.16 per 10Gy, p=0.126). Median PFS duration following durvalumab initiation was 14months, and median OS duration was 32months. Landmark analyses that excluded patients with progression or death within one year of durvalumab initiation demonstrated improved outcomes for patients who completed one year of durvalumab (2-year PFS 100% v. 40%, p<0.001; 2-year OS 100% v. 67%, p=0.862). Improved outcomes were observed for patients who received MHD below the cohort median (9.3Gy) compared to patients with higher MHD (median PFS 32months v. 8months, p<0.001; 2-year OS 69% v. 44%, p=0.088). For LA-NSCLC patients treated with CRT followed by immunotherapy, extent of cardiac irradiation may be a risk factor for immunotherapy discontinuation, disease recurrence, and death.

Metabolic response rates of epcoritamab + R-CHOP in patients with previously untreated (1L) high-risk diffuse large B-cell lymphoma, including double-hit/triple-hit lymphoma: Updated EPCORE NHL-2 data.

7519 Background: Patients (pts) with 1L diffuse large B-cell lymphoma (DLBCL) typically receive rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); however, around 40% relapse. Complete response rates and long-term outcomes are worse for high-risk pts with International Prognostic Index (IPI) 3–5 or double-hit/triple-hit lymphoma, representing an underserved pt population requiring better curative options. Data from the pivotal study of single-agent epcoritamab, a T-cell–engaging bispecific antibody, demonstrated impressive efficacy and a manageable safety profile (Thieblemont et al, JCO 2022). Preliminary data for epcoritamab + R-CHOP in 1L DLBCL (NCT04663347) showed encouraging efficacy. Here we present results for a larger cohort with longer follow-up. Methods: Pts with 1L CD20+ DLBCL and IPI ≥3 received subcutaneous epcoritamab (cycle [C] 1–4, QW; C5–6, Q3W) + R-CHOP for 6 Cs (21 d each) followed by epcoritamab monotherapy Q4W (28-d Cs) up to a total of 1 y. Results: As of Oct 31, 2022, 47 pts (median age, 64 y) had received epcoritamab 48 mg + R-CHOP with a median follow-up of 11.5 mo (range, 0.8–15.5). All pts had IPI 3–5, 37 (79%) had stage IV disease, and of 25 pts with FISH data available, 11 (44%) had double-hit/triple-hit DLBCL. Median time from diagnosis to first dose was 28 d (range, 3–423). Median dose intensity for R-CHOP was ≥95%. The most common treatment-emergent AEs (TEAEs) of any grade (G) were neutropenia (64%), anemia (62%), CRS (60%), fatigue (40%), pyrexia (40%), injection-site reactions (38%), and nausea (38%). TEAEs led to epcoritamab discontinuation in 3 pts; 1 pt had a G5 TEAE (COVID-19, unrelated to treatment). CRS was predominantly low grade (57% G1–2, 2% G3) and occurred mostly after the first full dose (C1D15); all cases resolved. One pt experienced G2 ICANS, which resolved. All response-evaluable pts (100%) had a response, and 76% had a complete metabolic response (CMR; Table). Notably, response rates were similar for double-hit/triple-hit pts (CMR rate, 82% [9/11]). The median durations of response, progression-free survival, and overall survival were not reached. Responses were durable; at 9 mo, an estimated 96% of pts with CMR remained in CMR. Updated data will be presented. Conclusions: Subcutaneous epcoritamab + R-CHOP induces high CMR rates with a manageable safety profile in pts with 1L high-risk DLBCL, including double-hit/triple-hit pts. These results support the ongoing phase 3 study of epcoritamab + R-CHOP in 1L pts (NCT05578976). Clinical trial information: NCT04663347 . [Table: see text]

Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial

BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110.

Pretreatment Pan-Immune-Inflammation Value Efficiently Predicts Survival Outcomes in Glioblastoma Multiforme Patients Receiving Radiotherapy and Temozolomide.

The purpose of this study was to determine the predictive significance of pretreatment pan-immune-inflammation value (PIV) in patients with newly diagnosed glioblastoma multiforme (GBM) who received postsurgical radiation (RT) and concurrent plus adjuvant temozolomide (TMZ). The outcomes of 204 newly diagnosed GBM patients were analyzed retrospectively. Each eligible patient's PIV was calculated using the findings of peripheral blood platelet (P), monocyte (M), neutrophil (N), and lymphocyte (L) counts obtained on the first day of therapy: PIV = P × M × N ÷ L. We used receiver operating characteristic (ROC) curve analysis to discover the ideal cutoff values for PIV concerning progression-free (PFS) and overall survival (OS) outcomes. The primary and secondary end-points were the OS and PFS divergences across the PIV groups. In ROC curve analysis, the optimal PIV cutoff was 385, which substantially interacted with PFS and OS results and categorized patients into low PIV (L-PIV; N = 75) and high PIV (H-PIV; N = 129) groups. Comparative survival analyses showed that the patients in the H-PIV group had significantly shorter median PFS (6.0 vs. 16.6 months; P < 0.001) and OS (11.1 vs. 22.9 months; P < 0.001) durations than those in the L-PIV group. The results of multivariate Cox regression analysis indicated an independent and significant connection between an H-PIV measure and shorter PFS and OS outcomes. The novel PIV was able to independently stratify newly diagnosed GBM patients into two groups with fundamentally different PFS and OS outcomes following RT and concurrent plus adjuvant TMZ.

Large-cell neuroendocrine carcinoma of the gynecologic tract: Prevalence, survival outcomes, and associated factors

We aimed to assess the clinical behavior of gynecologic large-cell neuroendocrine carcinoma (LCNEC) via a retrospective analysis of data from 469 patients. Patients diagnosed with gynecologic LCNEC from 1988 to 2015 were identified using the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox hazard regression analyses were performed to assess independent predictors of overall survival (OS) and cancer-specific survival (CSS). OS and CSS were also evaluated using the Kaplan-Meier method, and the effects of different treatment regimens on prognosis were compared according to disease stage. Cervical, ovarian, and endometrial LCNEC were observed in 169, 219, and 79 patients, respectively. The 5-year OS rates for patients with cervical, ovarian, and endometrial LCNEC were 35.98%, 17.84%, and 23.21%, respectively, and the median duration of overall survival was 26, 11, and 11 months in each group. The 5-year CSS rates for the three groups were 45.23%, 19.23%, and 31.39%, respectively, and the median duration of CSS was 41, 12, and 11 months in each group. Multivariate analysis revealed that American Joint Committee on Cancer stage, lymph node metastasis, and chemotherapy were independent prognostic factors for OS and CSS in patients with cervical LCNEC. Lymph node metastasis, surgery, and chemotherapy were independent prognostic factors for OS and CSS in the ovarian group and for OS in the endometrial group. Lymph node metastasis and surgery were also independent prognostic factors for CSS in the endometrial group. Surgery alone may help to improve overall survival and CSS in patients with early-stage cervical LCNEC. In contrast, surgery+chemotherapy and surgery+radiotherapy may help to improve survival in those with early-stage ovarian and endometrial LCNEC, respectively. Regardless of subtype, comprehensive treatment involving surgery, CTX, and RT should be considered to improve prognosis in patients with advanced-stage gynecologic LCNEC.

L-Mind: A Safety and Efficacy Analysis of Tafasitamab in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) Receiving Treatment for at Least 2 Years

Introduction Tafasitamab, is a humanized, Fc-modified anti-CD19 monoclonal antibody that functions as an immunotherapy through direct cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). Based on data from the ongoing, open-label, multicenter, single-arm, Phase II L-MIND study (NCT02399085; Salles, et al. Lancet Oncol 2020), tafasitamab in combination with lenalidomide (LEN) was granted accelerated approval in the US (2020) and conditional/accelerated approval by the EMA (2021) and other regulatory authorities for the treatment of adult patients with R/R DLBCL not otherwise specified, including DLBCL arising from low-grade lymphoma, and who are ineligible for autologous stem cell transplant (ASCT). It is a preferred regimen in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for this setting. We have previously reported long-term, durable clinical activity for tafasitamab + LEN (Duell, et al. Haematologica 2021). Here, we report efficacy and safety data for tafasitamab + LEN in patients with R/R DLBCL enrolled on L-MIND who received treatment for ≥2 years and those in follow-up for ≥5 years. Methods Patients were aged ≥18 years with ASCT-ineligible R/R DLBCL, 1-3 prior systemic therapies (including ≥1 CD20-targeting regimen), and an Eastern Cooperative Oncology Group performance status of 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg IV), once weekly during Cycles 1-3, with a loading dose on Day 4 of Cycle 1, then every 2 weeks (Q2W) during Cycles 4-12. LEN (25 mg orally) was administered on Days 1-21 of Cycles 1-12. After Cycle 12, progression-free patients received tafasitamab Q2W until disease progression. Time-to-event, treatment response (Cheson 2007), and safety endpoints were assessed. Results At data cut-off (February 15, 2022), of the 81 patients in the full analysis set, 30 patients completed 12 cycles of tafasitamab + LEN and 4 patients discontinued LEN before 12 cycles; 27 (34%) received treatment for ≥2 years (median: 4.3 years). The proportion of patients who were primary refractory, refractory to previous therapy, or who had received prior ASCT were similar between patients who received treatment for ≥2 years and the full analysis set (Table 1). Of the 27 patients who received treatment for ≥2 years, 23 are confirmed alive, one was lost to follow-up, one died by unknown cause, and two died following adverse events (AEs) unrelated to study treatment. Thirteen patients remained on treatment; reasons for tafasitamab discontinuation after ≥2 years were progressive disease (n=4), patient/physician decision (n=8), and non-treatment-related fatal AEs (n=2: one each for COVID-19 and cardiovascular AE). Twelve patients have been in follow-up for ≥5 years, of whom six are still on treatment, while 6 had discontinued treatment although still in response. In patients who received treatment for ≥2 years, 23 had previously achieved a complete response (CR) as a best response and four had a partial response (PR), as assessed by the investigator (Figure 1); the 48-month overall survival (OS) rate was 92.6%; however, the median duration of response, progression-free survival, and OS have not been reached. In patients refractory to previous therapy line (n=12), 91.7% were in follow-up at 48 months. All of the primary refractory patients (n=4) are in follow-up at 60 months. Of the six patients who received treatment for ≥5 years, five achieved CR (one of whom had triple-hit R/R DLBCL) and one had a PR (investigator-assessed). A lower incidence of AEs was reported during the tafasitamab monotherapy phase (Cycles 13-24 and Cycles ≥25) compared with the tafasitamab + LEN combination therapy phase (Cycles 1-12). The exposure-adjusted incidence of AEs showed that the majority were Grade 1-2. Conclusion Combination therapy with tafasitamab plus lenalidomide followed by tafasitamab monotherapy provided durable responses in patients with R/R DLBCL ineligible for ASCT. These long-term data suggest that this immunotherapy can achieve prolonged remission and survival of 5 years or longer in this patient population. The incidence of AEs decreased as patients transitioned from combination therapy to tafasitamab monotherapy, with long-term tafasitamab (up to 60 months) being well tolerated with no new safety signals. Funding MorphoSys AG Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Experience with Ruxolitinib Therapy for Steroid Refractory Acute Graft Versus Host Disease

AM and SML contributed equally as co-first authors. KJ and DK contributed equally as co-senior authors. Background Acute graft versus host disease (aGVHD) is a common complication of allogeneic hematopoietic stem cell transplant (alloHCT) and is associated with significant morbidity and mortality. Steroid refractory aGVHD (SR-aGVHD) carries a particularly grim prognosis. Ruxolitinib has shown promise for treatment of SR-aGVHD in phase 2 and 3 trials; however, safety and efficacy data outside of the clinical trial setting is lacking. We performed a multicenter retrospective study to examine the response to ruxolitinib and its efficacy in patients with SR-aGVHD in a Canadian population. Methods and Patients This multicenter retrospective study includes patients that underwent alloHCT between 2015 and 2021, across five Canadian transplant centers in Calgary, Toronto, Vancouver, Quebec City, and Saskatoon. Patients were included in the study if they developed at least overall grade 2 aGVHD, met the criteria of SR-aGVHD, and were started on ruxolitinib for SR-aGVHD. Data was recorded on standardized forms by independent reviewers across the five sites. Survival outcomes were calculated by Kaplan-Meier. Treatment failure was defined as 1) treatment switch due to no response/no benefit, 2) non-relapse mortality (NRM), 3) relapse of primary disease, or 4) intolerance leading to discontinuation. Failure-free survival (FFS) was calculated from ruxolitinib start until the event of treatment failure or latest follow-up, while overall survival (OS) was calculated from the day of starting ruxolitinib therapy until death or latest follow-up. Results We reviewed 59 patients treated with ruxolitinib for SR-aGVHD. The median age at time of ruxolitinib therapy was 53 (range 21-70) years, and 54.2% of patients were male. The most common indication for alloHCT was acute leukemia (48.2%), followed by myeloproliferative disorder/myelodysplastic syndrome (28.8%), lymphoma/chronic lymphocytic leukemia (18.6%), and others (5.1%). Approximately half of patients were treated with myeloablative conditioning (50.8%). Donor type included matched unrelated (44.1%), matched related (23.7%), mismatched unrelated (15.3%), haploidentical (15.3%) and cord blood (1.7%). The median onset of aGVHD was 65 days post alloHCT (range 15-265). Prior to initiation of ruxolitinib, most patients had overall grade 3 aGVHD (57.6%) and 16.9% had overall grade 4 disease. Patients had a median Karnofsky Performance Status (KPS) of 80% (range 30-100%) prior to ruxolitinib initiation. A total of 36 patients (61.0%) obtained a complete response (CR) or partial response (PR) at 28 days. At day 56, 31 patients (52.5%) obtained a CR or PR. Patients that achieved a CR or PR at day 28 had a higher survival rate (69.2%), compared with patients that did not (31.6%) (p=0.037). In terms of long-term outcomes, with a median follow-up of 391 days, OS at 12 months was 41.5% (95% CI, 27.6-54.8%), with a median OS duration of 5.3 months (Figure A). The 12 months' FFS rate was 29.1% (95% CI, 16.1-43.3%), with a median FFS of 2.6 months (Figure A). Reasons for failure included NRM (39.0%), need for therapy switch (18.6%), relapse of primary disease (5.1%), and intolerance (3.4%; Figure B). Within 12 months after starting ruxolitinib, 14.8% of surviving patients were able to successfully taper off without flare of their aGVHD. By 24 months, 23.6% of surviving patients were able to taper off glucocorticoids (Figure 1A). Glucocorticoid dose decreased over time with a mean daily prednisone dose 1.486±0.072 mg/kg at day 0 of ruxolitinib, compared to 0.152±0.038 mg/kg after 6 months (p<0.001). Nineteen patients (32.2%) had an initial ruxolitinib dose of 10 mg twice daily (BID) while 37 (66.1%) were started on 5 mg BID, then escalated to 10mg BID within 3-7 days per the REACH1 study. There was no significant difference in OS observed between patients started on 10 mg BID compared to 5 mg BID. Conclusions In this Canadian real-world experience-based study, we observed similar response rate and FFS rate that was found in the REACH2 trial for SR-aGVHD treated with ruxolitinib. We also observed that NRM was the primary reason for treatment failure, and saw that ruxolitinib therapy for SR-aGVHD enabled successful tapering of prednisone. Overall, these data support clinical trial evidence for ruxolitinib as useful therapeutic option for SR-aGVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase 1b study of cobimetinib plus atezolizumab in patients with advanced BRAFV600 wild-type melanoma progressing on prior anti–programmed death-1 therapy

ObjectiveTo evaluate the efficacy and safety of cobimetinib plus atezolizumab in the treatment of patients with advanced BRAFV600 wild-type melanoma who had progressed on prior anti‒programmed death-1 (PD-1) therapy. Patients and methodsThis phase 1b, open-label, international multicentre study enrolled 3 cohorts. Herein, we report on patients in cohorts A and B who had progressed on prior anti‒PD-1 therapy. Patients in cohort A received cobimetinib 60 mg once daily for 21 days followed by a 7-day break and concurrent intravenous atezolizumab 840 mg every 2 weeks. Patients in cohort B received the same dosing regimen as cohort A except for cycle 1 in which patients received cobimetinib only for the first 14 days prior to initiation of atezolizumab on cycle 1 day 15. Coprimary end-points were objective response rate and disease control rate. Secondary end-points were duration of response, progression free survival and overall survival. ResultsBetween 19th June 2017 and 12th December 2018, 103 patients were enrolled. Median follow-up was 6.9 months (interquartile range, 4.8–10.1 months); objective response rate was 14.6% and disease control rate was 38.8% (95% confidence interval, 29.39–48.94). The median duration of response, progression-free survival and overall survival was 12.7 months, 3.8 months and 14.7 months, respectively. The most common adverse events were diarrhoea (75/103; 72.8%), dermatitis acneiform (57/103; 55.3%) and nausea (52/103; 50.5%). Thirty-four patients (33.0%) died: 33 (91.7%) due to progressive disease and one (1%) due to treatment-related oesophagitis. ConclusionsCombination therapy with cobimetinib and atezolizumab in patients with advanced BRAFV600 wild-type melanoma with disease progression on or after prior anti‒PD-1 therapy demonstrated limited activity. Clinical trial registrationThis study is registered with ClinicalTrials.gov; NCT03178851;