Secondary Endpoint Of Overall Survival Research Articles

IMMU-30. IGV-001: A BIOLOGIC-DEVICE COMBINATION PRODUCT ELICITS POTENT ANTI-GBM RESPONSES AS A MONOTHERAPY AND IN COMBINATION WITH CHECK POINT INHIBITION

Abstract INTRODUCTION Imvax is developing GoldspireTM, a personalized immunotherapy that combines whole tumor-derived cells with an antisense oligonucleotide against insulin-like growth factor 1 receptor (IGF-1R; IMV-001) in biodiffusion chambers (BDCs; 0.1 µm pore). BDCs are irradiated and implanted at abdominal sites for ~48h to deliver an antigenic payload and immunostimulatory factors that together train the immune system to attack tumor cells. The lead product, IGV-001, was evaluated in newly diagnosed glioblastoma (ndGBM) patients in a phase 1b study. Median overall survival (OS) of highest exposure IGV-001-treated Stupp-eligible patients (n=10) was 38.2 mos compared with 16.2 mos in standard-of-care-treated patients (p=0.044; ClinicalTrials.gov NCT02507583). A Phase 2b study in ndGBM is currently underway (ClinicalTrials.gov NCT04485949), where a primary endpoint of progression-free survival and key secondary endpoints of overall survival and safety will be evaluated. METHODS The orthotopically implanted GBM (luciferase-expressing GL261-luc2) model was utilized to evaluate the efficacy of mIGV-001 (the murine version of IGV-001) alone or in combination with anti-PD-1 immunotherapy. The following four groups were compared: mIGV-001 or BDC placebo + isotype or anti-PD-1 antibody (4 doses total every 3-4 days). GL261-luc2 cells were treated with IGF-1R antisense IMV-001. The treated cell suspension was loaded into clinical-grade BDCs (0.1-µm pore size, polyvinylidene difluoride membrane) at a density of 1 × 106 cells per BDC and then irradiated with 5–6 Gy. mIGV-001 or BDCs filled with saline were administered 28 days prior to tumor challenges and tumor progression and survival were monitored for an additional 100 days. RESULTS Preventative treatment with mIGV-001 limited tumor progression and extended OS in mice orthotopically (i.e., intracranially) challenged with GL261-luc2 cells. The therapeutic benefit of mIGV-001 was enhanced with anti-PD-1 treatment and the combination therapy was superior to either monotherapy.

Phase II study of neoadjuvant durvalumab and tremelimumab in combination with gemcitabine and cisplatin in patients with intrahepatic cholangiocarcinoma that is borderline resectable or resectable with high risk for recurrence.

TPS4198 Background: Finding effective and tolerable neoadjuvant treatment to downstage borderline resectable intrahepatic cholangiocarcinoma (ICC) could increase the rate of R0 resections and significantly improve patient outcomes. The combination of gemcitabine, cisplatin, and durvalumab based on the TOPAZ-1 trial is now the preferred first-line regimen for advanced, unresectable biliary tract cancer (1). The objective response rate (ORR) was 26.7% for the 3-drug regimen. Gemcitabine, cisplatin, durvalumab, and tremelimumab (an anti-CTLA4 antibody) in advanced, unresectable biliary tract cancer had an objective response rate of 70% in a phase II study (2). Given this response to immunotherapy plus chemotherapy, the 4-drug combination of gemcitabine, cisplatin, durvalumab, plus tremelimumab in the neoadjuvant setting may be able to improve the conversion rate of borderline resectable ICC to resectable ICC and improve R0 resection rates. Methods: This is an open-label, single-arm, multicenter phase II safety and feasibility study of neoadjuvant gemcitabine + cisplatin + durvalumab + tremelimumab in patients with ICC that is borderline resectable or resectable with a high risk of recurrence. 24 patients will receive 3-week cycles of durvalumab 1500 mg on D1, tremelimumab 300 mg only on C1D1, gemcitabine 1000mg/m2 on D1 and D8, and cisplatin 25mg/m2 on D1 and D8. Treatment will be stopped after C4 if a patient is able to proceed with surgery, otherwise they will complete 8 cycles and be re-evaluated for surgery at that point. Key eligibility criteria include no prior systemic therapy, histologically proved ICC, ECOG 0-1, and disease that is not readily suitable for resection with curative intent based on discussion with multidisciplinary committee including a hepatobiliary surgeon. Primary endpoints are feasibility and safety with secondary endpoints of overall survival, progression free survival, ORR, R0 resection rate, and pathologic complete response. Molecular biomarkers from blood to predict outcomes and organoid development from circulating tumor cells are exploratory endpoints. The study will be carried out in 2 stages. In stage 1, 11 patients will be accrued and the study will be stopped if 2 or fewer patients undergo resection based on a null hypothesis of a resection rate after neoadjuvant treatment of about 24%. Otherwise, 17 more patients will be accrued in stage 2 (assuming 15% dropout rate to hit target of 24) and if 9 or more of the 24 patients undergo resection, we will claim the treatment is feasible. The design has a type 1 error rate of 0.1 and power 0.8. Patient follow-up will be up to 3 years. The study is currently enrolling participants. 1. Oh et al. NEJM Evid 2022. 2. Oh et al. Lancet Gastroenterol Hepatol 2022. Clinical trial information: NCT06017297 .

Abstract PO2-04-07: Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials

Abstract Background: The numerous but conflicting first-line treatment regimens for Her-2 positive advanced breast cancer necessitate a comprehensive evaluation to inform clinical decision-making. In this study, we conducted a Bayesian network meta-analysis (NMA) to compare the efficacy and safety of different interventions. Methods: We systematically searched for relevant randomized controlled trials (RCTs) in Pubmed, Embase, Cochrane Library and online abstracts published by ASCO, SABCS. NMA was performed using R software, STATA and Review Manager 5.4 to calculate and analyze the primary endpoint progression free survival (PFS), as well as the secondary endpoints of overall survival (OS), objective response rate (ORR) and adverse events (AE) higher than grade 3. Results: Out of the 8,603 manuscripts retrieved, we included 30 RCTs involving 12,045 patients in our analysis. Regarding PFS, the combination of trastuzumab with TKI was more favorable than dual-target therapy (hazard ratio=0.54, 95% [CI]: 0.40–0.72), and combination chemotherapy was superior to monotherapy (HR=0.66, 0.53-0.83). It is important to note that the addition of anthracycline did not result in improved PFS (HR=1.27, 0.87-1.86). For the HR+HER2+ population, dual-target plus endocrine therapy was more effective than single-target plus endocrine therapy (HR=0.65, 0.53-0.80). Monotherapy combined with dual-target therapy significantly improved OS and ORR compared to monotherapy with single-target therapy (HR=0.69, 0.56-0.84; OR=1.89, 1.34-2.65). A comprehensive analysis of both PFS and AE higher than grade 3 indicated that monotherapy plus dual-target therapy struck a balanced approach between effectiveness and toxicity compared to other regimens. Conclusions: Monotherapy plus dual-target therapy remains the optimal choice among all first-line treatment options for advanced breast cancer. The combination of trastuzumab with TKI demonstrated a significant improvement in PFS, but further data are warranted to confirm the survival benefit. Figure 1. Network diagrams of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. Figure 2. Forest plot of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. (A): PFS of HER2+ for experimental arms. (B): PFS of HR+ and HER2+ for experimental arms. (C): OS of HER2+ for experimental arms. (D): ORR of HER2+ for experimental arms. (E): Adverse events higher than grade 3 of HER2+ for experimental arms. Figure 3. Each endpoint ranking for experimental arms. (SUCRA, surface under the cumulative ranking) (A): PFS ranking for experimental arms. (B): OS ranking for experimental arms. (C): ORR ranking for experimental arms. (D): Adverse events higher than grade 3 ranking for experimental arms. (E): Experimental arms ordered by their overall probability as the best treatment in terms of both efficacy and safety Citation Format: Junxiao Wang, Yushuai Yu, Jie Zhang, Chuangui Song. Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-07.

Multi-Level fusion graph neural network: Application to PET and CT imaging for risk stratification of head and neck cancer

Background and objectiveRisk stratification of head and neck cancer (HNC) patients is important to settle individualized treatment strategies. This study proposed a multi-level fusion graph neural network (MLF-GNN) that fuses PET/CT image features and clinical data for improved prognosis prediction of HNC patients. MethodsThis study exploited 642 HNC patients from 7 different centers collected from The Cancer Imaging Archive (TCIA), which were arbitrarily separated into 507 patients from 4 centers for training and internal validation, and 135 patients from 3 centers for external testing. We constructed a population graph with edges representing the similarity between patients and the vertices representing radiomics features. Single-modality GNN models and MLF-GNN models by using feature-fusion and network-fusion strategies were constructed for progression-free survival (PFS) prediction, respectively. Model performance was evaluated by the concordance index (C-index), area under the receiver operator characteristic curve (ROC-AUC), and Kaplan–Meier curves. ResultsCompared with the single-modality GNN models and feature-fusion based MLF-GNN model, the network-fusion based MLF-GNN model achieved the highest C-index of 0.788 (95 % CI: 0.727–0.848) and AUC of 0.807 (95 % CI: 0.731–0.870) for PFS prediction in the external testing set. Besides, it also showed good performance on the secondary endpoints of overall survival (OS), recurrence-free survival (RFS), and metastasis-free survival (MFS) in the external testing set, with C-index of 0.800 (95 % CI: 0.729–0.871), 0.823 (95 % CI: 0.763–0.884) and 0.758 (95 % CI: 0.673–0.844), respectively. Subgroup analysis stratified with pathogenic site and treatment type showed that the proposed method has good prediction performance on subgroup risk stratification. ConclusionsThe proposed MLF-GNN model could capture the topological relationships among patients by taking full advantage of multi-modality imaging data and clinical data, which achieved improved prognostic performance and was beneficial to guide individual treatment.

Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study

The optimal perioperative chemotherapy for patients with muscle-invasive bladder cancer is not defined. The VESPER (French Genito-Urinary Tumor Group and French Association of Urology V05) trial reported improved 3-year progression-free survival with dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) versus gemcitabine and cisplatin (GC) in patients who received neoadjuvant therapy, but not in the overall perioperative setting. In this Article, we report on the secondary endpoints of overall survival and time to death due to bladder cancer at 5-year follow-up. VESPER was an open-label, randomised, phase 3 trial done at 28 university hospitals or comprehensive cancer centres in France, in which adults (age ≤18 years and ≤80 years) with primary bladder cancer and histologically confirmed muscle-invasive urothelial carcinoma were randomly allocated (1:1; block size four) to treatment with dd-MVAC (every 2 weeks for a total of six cycles) or GC (every 3 weeks for a total of four cycles). Overall survival and time to death due to bladder cancer (presented as 5-year cumulative incidence of death due to bladder cancer) was analysed by intention to treat (ITT) in all randomly assigned patients. Overall survival was assessed by the Kaplan-Meier method with the treatment groups compared with log-rank test stratified for mode of administration of chemotherapy (neoadjuvant or adjuvant) and lymph node involvement. Time to death due to bladder cancer was analysed with an Aalen model for competing risks and a Fine and Gray regression model stratified for the same two covariates. Results were presented for the total perioperative population and for the neoadjuvant and adjuvant subgroups. The trial is registered with ClinicalTrials.gov, NCT01812369, and is complete. From Feb 25, 2013, to March 1, 2018, 500 patients were randomly assigned, of whom 493 were included in the final ITT population (245 [50%] in the GC group and 248 [50%] in the dd-MVAC group; 408 [83%] male and 85 [17%] female). 437 (89%) patients received neoadjuvant chemotherapy. Median follow-up was 5·3 years (IQR 5·1-5·4); 190 deaths at the 5-year cutoff were reported. In the perioperative setting (total ITT population), we found no evidence of association of overall survival at 5 years with dd-MVAC treatment versus GC treatment (64% [95% CI 58-70] vs 56% [50-63], stratified hazard ratio [HRstrat] 0·79 [95% CI 0·59-1·05]). Time to death due to bladder cancer was increased in the dd-MVAC group compared with in the GC group (5-year cumulative incidence of death: 27% [95% CI 21-32] vs 40% [34-46], HRstrat 0·61 [95% CI 0·45-0·84]). In the neoadjuvant subgroup, overall survival at 5 years was improved in the dd-MVAC group versus the GC group (66% [95% CI 60-73] vs 57% [50-64], HR 0·71 [95% CI 0·52-0·97]), as was time to death due to bladder cancer (5-year cumulative incidence: 24% [18-30] vs 38% [32-45], HR 0·55 [0·39-0·78]). In the adjuvant subgroup, the results were not conclusive due to the small sample size. Bladder cancer progression was the cause of death for 157 (83%) of the 190 deaths; other causes of death included cardiovascular events (eight [4%] deaths), deaths related to chemotherapy toxicity (four [2%]), and secondary cancers (four [2%]). Our results on overall survival at 5 years were in accordance with the primary endpoint analysis (3-year progression-free survival). We found no evidence of improved overall survival with dd-MVAC over GC in the perioperative setting, but the data support the use of six cycles of dd-MVAC over four cycles of GC in the neoadjuvant setting. These results should impact practice and future trials of immunotherapy in bladder cancer. French National Cancer Institute.

The ZR2-Minichop Study：Zanubrutinib, Lenalidomide, Rituximab, Cyclophosphamide, Vincristine, Epirubicin and Prednisone in Elderly Patients with Previously Untreated Diffuse Large B-Cell Lymphoma

Background: Diffuse large B cell lymphoma (DLBCL) is common in the elderly group. New schedules are required due to the toxicity in classic chemotherapy regimens. Previous studies reported that non-germinal center B cell (non-GCB) subtype aggregates in elderly patients with abnormality in the activated B cell receptor signal and nuclear factor kappa-B pathway. We conducted a prospective trial to investigate the efficacy and safety of the ZR2-miniCHOP schedule (zanubrutinib, lenalidomide, rituximab, cyclophosphamide, vincristine, epirubicin and prednisone) in elder patients newly diagnosed with non-GCB DLBCL. Methods: This multicenter, single-arm, phase II clinical study started in June 2021 at 6 centers in China. Eligible patients were newly diagnosed non-GCB DLBCL, aged 60 to 80 with Eastern Cooperation Oncology Group (ECOG) performance status over 2, or patients aged over 80 with ECOG status of 0-4. The purpose of this study is to discuss the response, safety and long-term survival with the primary endpoint of objective response rate (ORR) and the secondary endpoint of overall survival (OS) and progression free survival (PFS). Patients would receive 2 cycles induction period with zanubrutinib 160mg twice per day on d1-28, lenalidomide 25mg d1-10 and rituximab 375mg/m 2 d1, after then combine 4-6 cycles miniCHOP schedule as: cyclophosphamide 400mg/m 2 d2, vincristine 1.4mg/m 2 d2, epirubicin 35mg/m 2 d2 and prednisone 45mg/m 2 d2-6. Evaluation is conducted after 6 cycles of treatment including the ORR and CR rate by positron emission tomography-computed tomography (PET-CT) and 2-years OS and PFS. Results: At the data collection duration from June 2021 to June 2023, 45 patients were recruited in this trial. 34 patients were considered for result analysis as 2 withdrawals and 1 drop-out. 6 patients are still in the process of treatment. The median age of the 45 patients enrolled was 79 (range 65-90) years, with 34 (75.6%) patients over 75 years old. The ORR was 91.2% (31/34). Among the 34 assessable patients, 61.8% (21/34) of them reached CR after 6 cycles routine therapy. Besides, 29.4% (10/34) patients just achieved PR, and for these patients we then continued administered more 2 cycles with ZR2+miniCHOP. Later 5 of these 10 patients achieved CR. One patient stayed SD and 3 patients appeared disease progressing. The most common hematology-relevant adverse events (AEs) were neutropenia (13/34) and thrombocytopenia (10/34). Eleven patients appeared AEs over grade 3 occurred during therapy with neutropenia, thrombocytopenia, infectious pneumonia events. All these patients have been administrated the normal dose as the treatment resistance and the toxicity did not affect therapy. Two patients died of progressive disease. No treatment-associated death was observed. Generally analyzing, this trial achieved acceptable response and safety. Conclusion: The ZR2-miniCHOP schedule represented satisfactory efficacy and safety in elderly non-GCB DLBCL.

Ongoing Phase III Randomized Trial of Salvage DFP-10917 Vs. Non-Intensive Reinduction or Intensive Reinduction for Acute Myelogenous Leukemia (AML)

Background: DFP-10917 is a deoxycytidine analogue with a novel structure. It contains a side chain cyanide (CN) group at the 2 carbon of deoxyribose that induces DNA damage in a manner unique from structurally related nucleoside analogues (eg, cytarabine, decitabine, or gemcitabine). When administered at high doses, DFP-10917 inactivates deoxyribonucleic acid (DNA) polymerase leading to S-phase arrest similar to cytarabine. When administered at low concentrations by continuous infusion, it displays an alternative, potentially advantageous, mechanism of action - DNA strand breakage leading to G2/M phase arrest and ultimately cell apoptosis. The strand breakage occurs via a spontaneous beta elimination reaction that requires no additional enzymatic activity. There is no current standard treatment for patients with relapsed/refractory (R/R) AML. Results of a completed Phase I/II study in R/R AML (D11-11002; NCT01702155) demonstrated preliminary efficacy of DFP-10917 in this indication, with a ~50% complete response (CR) rate in Phase II. Five of 14 patients who achieved CR proceeded to stem cell transplantation. Based on completed studies, risks associated with DFP-10917 are predominantly hematological (eg, neutropenia, anemia, febrile neutropenia, leukopenia, lymphopenia, thrombocytopenia). Study Design and Methods: Based on promising Phase II results, the Sponsor initiated Study D18-11141 (NCT03926624), a Phase III, randomized, controlled study to compare the rate and duration of CR in patients with AML R/R to 2-4 prior induction regimens. Patients receive either DFP-10917 or non-intensive reinduction (low-dose cytarabine [LoDAC], azacitidine, decitabine, venetoclax + LoDAC or azacitidine or decitabine) or intensive reinduction (high and intermediate dose cytarabine regimens). Patients assigned to DFP-10917 receive 6 mg/m 2/day by continuous infusion for 14 days followed by a 14-day rest period. Control treatment is administered per physician's decision. Adults aged ≥18 years with histologically or pathologically confirmed diagnosis of AML based on World Health Organization classification and adequate performance status (≤2) and organ function are eligible. Study Status: The study is ongoing at 34 study centers in the United States. As of July 2023, 162 patients were enrolled, with 82 assigned to DFP-10917. A majority of the patients are male (57.4%) and aged <75 years (83.3%). Overall, 44% have AML with myelodysplasia-related changes; 36% have AML not otherwise specified; and <20% have AML with recurrent genetic abnormalities or therapy-related myeloid neoplasms. Enrollment and management of patients were affected from 2020 to 2021 by COVID-19 restrictions. A prospectively-planned interim analysis will occur after the 150 th patient randomized is followed for >2 months. Based on recruitment projections, this analysis is scheduled for 09/2023. At that time, the Data Safety Monitoring Board will review an unblinded estimate of the treatment effect for the primary endpoint of CR, with the study either stopped for superiority or futility or continuing to a final analysis. If continued, the number of patients required for the final analysis will range from 300 to 450, in increments of 50, with the number determined based on the size of the interim treatment effect for the primary endpoint of CR or the secondary endpoint of overall survival.

CTIM-19. ONCOLYTIC DNX-2401 VIROTHERAPY PLUS PEMBROLIZUMAB IN RECURRENT GLIOBLASTOMA: A PHASE 1/2 TRIAL

Abstract Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2–20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12months was 52.7% (95% CI 40.1–69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5months (10.7–13.5months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05–0.87). A total of 56.2% (95% CI 41.1–70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (APOLLO): extended follow up of an open-label, randomised, multicentre, phase 3 trial

The primary analysis of the APOLLO trial, done after a median follow-up of 16·9 months, showed that daratumumab plus pomalidomide and dexamethasone significantly improved progression-free survival versus pomalidomide and dexamethasone. Here, we report the final overall survival and updated safety results from APOLLO. APOLLO was an open-label, randomised, phase 3 trial conducted at 48 academic centres and hospitals across 12 countries in Europe, that included adults aged 18 years or older with relapsed or refractory multiple myeloma who had an ECOG performance status score of 0-2, had received at least one previous line of therapy, including lenalidomide and a proteasome inhibitor, had a partial response or better to one or more previous lines of antimyeloma therapy, and were refractory to lenalidomide if they had received only one previous line of therapy. An interactive web-response system was used to randomly assign patients (1:1) to receive daratumumab plus pomalidomide and dexamethasone or pomalidomide and dexamethasone; patients were stratified by the number of previous lines of therapy and International Staging System disease stage. Oral pomalidomide (4 mg once daily; days 1-21) and dexamethasone (40 mg once daily; days 1, 8, 15, and 22) were given in 28-day cycles until disease progression or unacceptable toxicity. Daratumumab (1800 mg subcutaneously or 16 mg/kg intravenously) was administered weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks thereafter. The primary endpoint of progression-free survival, which has previously been reported, and the pre-planned secondary endpoint of overall survival were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03180736) and is no longer enrolling patients. Between June 22, 2017, and June 13, 2019, 304 patients were randomly assigned: 151 to the daratumumab plus pomalidomide and dexamethasone group and 153 to the pomalidomide and dexamethasone group. The median age was 67 years (IQR 60-72); 143 (47%) patients were female and 161 (53%) were male, and 272 (89%) were White. At a median follow-up of 39·6 months (IQR 37·1-43·7), median overall survival was 34·4 months (95% CI 23·7-40·3) in the daratumumab plus pomalidomide and dexamethasone group versus 23·7 months (19·6-29·4) in the pomalidomide and dexamethasone group (hazard ratio [HR] 0·82 [95% CI 0·61-1·11]; p=0·20). The most common grade 3-4 treatment-emergent adverse events were neutropenia (103 [69%] of 149 with daratumumab plus pomalidomide and dexamethasone vs 76 [51%] of 150 with pomalidomide and dexamethasone), anaemia (27 [18%] vs 32 [21%]), and thrombocytopenia (27 [18%] vs 28 [19%]). Serious treatment-emergent adverse events occurred in 80 (54%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group and in 60 (40%) of 150 patients in the pomalidomide and dexamethasone group, the most common of which was pneumonia (23 [15%] of 149 vs 13 [9%] of 150). Treatment-emergent adverse events resulting in death occurred in 13 (9%) of 149 patients in the daratumumab plus pomalidomide and dexamethasone group and in 13 (9%) of 150 patients in the pomalidomide and dexamethasone group, with 4 (3%) of 151 adverse events leading to death within 30 days of the last treatment dose thought to be related to study treatment in the daratumumab plus pomalidomide and dexamethasone group (septic shock [n=1]; sepsis [n=1]; bone marrow failure, campylobacter infection, and liver disorder [n=1]; and pneumonia [n=1]) and none in the pomalidomide and dexamethasone group. Although the difference in overall survival observed between treatment groups was not significant, the safety profile results with long-term follow-up reported here continue to support the use of daratumumab plus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. European Myeloma Network and Janssen Research & Development.

Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer

BackgroundPreclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory...

Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial

Association with hypomethylating agents is a promising strategy to improve the efficacy of immune checkpoint inhibitors-based therapy. The NIBIT-M4 was a phase Ib, dose-escalation trial in patients with advanced melanoma of the hypomethylating agent guadecitabine combined with the anti-CTLA-4 antibody ipilimumab that followed a traditional 3 + 3 design (NCT02608437). Patients received guadecitabine 30, 45 or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks starting on week 0 for a total of four cycles, and ipilimumab 3 mg/kg intravenously starting on day 1 of week 1 every 3 weeks for a total of four cycles. Primary outcomes of safety, tolerability, and maximum tolerated dose of treatment were previously reported. Here we report the 5-year clinical outcome for the secondary endpoints of overall survival, progression free survival, and duration of response, and an exploratory integrated multi-omics analysis on pre- and on-treatment tumor biopsies. With a minimum follow-up of 45 months, the 5-year overall survival rate was 28.9% and the median duration of response was 20.6 months. Re-expression of immuno-modulatory endogenous retroviruses and of other repetitive elements, and a mechanistic signature of guadecitabine are associated with response. Integration of a genetic immunoediting index with an adaptive immunity signature stratifies patients/lesions into four distinct subsets and discriminates 5-year overall survival and progression free survival. These results suggest that coupling genetic immunoediting with activation of adaptive immunity is a relevant requisite for achieving long term clinical benefit by epigenetic immunomodulation in advanced melanoma patients.

Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial.

LBA500 Background: RIB + ET has demonstrated significant survival benefits in pre- and postmenopausal pts with HR+/HER2− metastatic BC. To investigate whether RIB + ET also improves outcomes in early BC (EBC), the Phase III NATALEE trial (NCT03701334) evaluated adjuvant RIB + ET in a broad population of pts with stage II or III HR+/HER2− EBC at risk for recurrence, including pts with no nodal involvement (N0). As extended duration of tx is crucial to prolong cell cycle arrest and drive more tumor cells into senescence or death, a 3-y duration of RIB tx at a dose of 400 mg was chosen to improve tolerability while maintaining efficacy. Results from a prespecified interim analysis of invasive disease–free survival (iDFS; primary endpoint) are presented. Methods: Men and pre- or postmenopausal women were randomized 1:1 to RIB (400 mg/day; 3 wk on/1 wk off for 3 y) + ET (letrozole 2.5 mg/day or anastrozole 1 mg/day, for ≥ 5 y) or ET alone. Men and premenopausal women also received goserelin. Eligible pts had an ECOG PS of 0-1 and BC anatomic stage IIA (either N0 with additional risk factors or 1-3 axillary lymph nodes [N1]), stage IIB, or stage III per AJCC (8th ed); prior (neo)adjuvant ET was allowed if initiated ≤ 12 mo before randomization. Stratification factors were menopausal status, disease stage, prior (neo)adjuvant chemotherapy, and geographic region. This prespecified interim analysis of iDFS, defined per STEEP criteria, was planned after ≈ 425 iDFS events (≈ 85% of planned total events). iDFS was evaluated by Kaplan-Meier methods, and statistical comparison was made by a stratified log-rank test, with a protocol-defined Lan-DeMets (O'Brien-Flemming) stopping boundary of a 1-sided P < .0128 for superior efficacy. Results: From 10 Jan 2019 to 20 April 2021, 5101 pts were randomized (RIB+ET, n = 2549; ET alone, n = 2552). As of the data cutoff (11 Jan 2023), median follow-up was 34 mo (min, 21 mo). 3- and 2-y RIB tx was completed by 515 pts (20.2%) and 1449 pts (56.8%), respectively; 3810 (74.7%) remained on study tx (RIB+ET, n = 1984; ET alone, n = 1826). iDFS was evaluated after 426 events (RIB + ET, n = 189; ET alone, n = 237). RIB + ET demonstrated significantly longer iDFS than ET alone (HR, 0.748; 95% CI, 0.618-0.906; P = .0014); 3-y iDFS rates were 90.4% vs 87.1%. iDFS benefit was generally consistent across stratification factors and other subgroups. Secondary endpoints of overall survival, recurrence-free survival, and distant disease–free survival consistently favored RIB. RIB at 400 mg had a favorable safety profile with no new signals. Conclusions: Ribociclib added to standard-of-care ET demonstrated a statistically significant, clinically meaningful improvement in iDFS with a well-tolerated safety profile. The NATALEE results support ribociclib + ET as the treatment of choice in a broad population of pts with stage II or III HR+/HER2− EBC, including pts with N0 disease. Clinical trial information: NCT03701334 .

Associations of diet with survival of patients (pts) with metastatic cancer of the urothelium (mUC) and renal cell carcinoma (mRCC) on immune checkpoint blockade (ICB).

4598 Background: The gut microbiome is an emerging modifiable predictor of ICB efficacy. Diet impacts the gut microbiome and fiber intake is associated with longer progression-free survival (PFS) in advanced melanoma treated with ICB. Whether diet impacts ICB benefit in mUC or mRCC remains unknown. Methods: Using a prospective cohort design, baseline dietary data were collected from pts with mUC or mRCC initiating ICB at Memorial Sloan Kettering Cancer Center using the extensively validated Harvard Willett Food Frequency Questionnaire. Tumor mutational burden (TMB) was estimated by next generation sequencing (MSK-IMPACT). The primary endpoint was radiologist assessed PFS, with secondary endpoint of overall survival (OS). Fiber intake was stratified as high or low using the median intake in our cohort. Associations between fiber intake and clinical outcomes were assessed using Kaplan-Meier curves plus univariable (UV) and multivariable (MV) Cox proportional hazards regression. Models were adjusted for prior ICB exposure. Models for mUC controlled for TMB and Bellmunt risk factors. Models for mRCC controlled for histology (clear vs non-clear cell) and IMDC risk score. Results: From 2/2021-6/2022, 88 pts eligible for analysis were enrolled with median follow-up of 10.1 months (mo) (mUC n = 40; mRCC n = 48). Median fiber intake was 17.5 g/day (interquartile range 12.5-24.5). Among pts with mUC, high fiber intake (≥17.5 g/day) was associated with longer PFS (UV hazard ratio [HR] 0.56, 95% CI 0.26-1.19, p = .13; MV HR 0.39, 95% CI 0.16-0.93, p = .03). Similar trends were observed for mRCC. In subgroup analyses, PFS was numerically longer with high fiber intake among mUC pts on maintenance avelumab (median PFS 6.1 vs 3.0 mo, n = 14) and in pts with mRCC treated with first-line (1L) ipilimumab + nivolumab (median PFS 18.0 vs 5.7 mo, n = 14) and 1L ICB + tyrosine kinase inhibitor (median PFS not reached vs 5.1 mo, n = 21). Among pts with mUC on non-maintenance ICB, pts with high fiber intake had numerically higher PFS at 6 mo (38% vs 14%, n = 26). Conclusions: This pilot study indicates that high fiber intake is associated with longer PFS among pts with mUC on ICB. Trends towards longer PFS and OS with high fiber intake were observed among pts with mRCC. Analyses of the gut microbiome are underway to investigate mechanisms of action. [Table: see text]

Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial

Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2–20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1–69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7–13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05–0.87). A total of 56.2% (95% CI 41.1–70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406).

109P Updated long-term overall survival of older adjuvant ibandronate-treated patients with intermediate- or high-risk early breast cancer compared with additional adjuvant capecitabine treatment: The ICE randomized clinical trial

The majority of breast cancers occur in women over the age of 65, but older breast cancer patients are largely underrepresented in clinical trials. We investigated the effect of adding capecitabine to adjuvant treatment with ibandronate in elderly breast cancer patients. The multicenter phase III ICE trial enrolled women ≥65 years with early node-positive/high-risk node-negative breast cancer and a Charlson Comorbidity Index (CCI) ≤2. Patients were randomized to capecitabine 2000 mg/m2 day 1-14 q3w for 6 cycles plus ibandronate (50 mg p.o. daily or alternatively 6 mg i.v. q4w) or ibandronate alone for 2 years. We present here an update on long-term follow-up for the secondary endpoint of overall survival (OS). 1358 (96.4%) from 1409 randomized patients started treatment. 564 (83.4%) completed 6 cycles of capecitabine. 513 (77.7%) and 516 (78.8%) completed ibandronate in the capecitabine/ibandronate and ibandronate arm, respectively. Median age was 71 (range 64-88) years, 1099 (81%) were hormone receptor (HR)-positive, 705 (51.9%) node-negative, 794 (58.5%) had a CCI of 0. HR-positive patients received additional adjuvant endocrine treatment. After an updated median follow-up time of 74 (IQR 56-126) months for OS in the entire cohort, 7-year OS was 83.5% for capecitabine/ibandronate versus 80.9% for ibandronate, and 10-year OS was 73.1% for capecitabine/ibandronate versus 70.8% for ibandronate (P=0.413). Lack of effect was independent from age, nodal and HR status. Addition of capecitabine caused significantly higher skin and gastrointestinal toxicities. The adjuvant combination of capecitabine and ibandronate did not show significantly better OS than ibandronate alone in elderly breast cancer patients.

Abstract PD8-04: The role of Yoga as a complementary therapy in women undergoing treatment for breast cancer: A randomized controlled trial

Abstract Background: Yoga has been tested in multiple small-randomized studies for its impact on quality of life (QOL) on breast cancer (BC). We conducted a randomized controlled trial, to study the effect of yoga on disease free survival as the primary endpoint in women with operable breast cancer. (NCT02161900). Methods: Women with non-metastatic BC during and after standard treatment, were randomized to yoga and conventional exercise(YCE) versus conventional exercise only(CE). The primary endpoint was disease free survival (DFS) with secondary endpoints of overall survival (OS) and QOL, which was assessed using the EORTC QLQC30, BR23, Brief fatigue inventory (BFI), Visual pain scores (VPS) and a spirituality questionnaire (SQ). EORTC QLQ was assessed at baseline (BL), 6-9 months (mo), 18-21 mo. BFI and VPS at BL, 6-8 mo and 12-15 mo and SQ at BL and 12-15 mo. We report the final analysis of DFS, OS and QOL in 850 women randomized to the study. The groups were balanced for clinic-pathologic factors in both arms. Results: Of the 850 women randomized on the study, 426 were on YCE arm and 424 on CE arm. The median age was 47 versus (vs) 48 years, median pT size was 3 vs 2.85cm, grade 3 tumors were 82.7 vs 82.1%, hormone receptor positive was in 69% vs 69.4% and HER2neu positive was in 14.4 vs13.7% in YCE and CE arms respectively. At a median follow-up of 80 months the disease fee survival was 80% vs 76.7% (HR= 0.85, 95% CI= 0.64 – 1.14, p=0.28), and overall survival was 85.4% vs 83.1% (HR= 0.86, 95%CI = 0.61 – 1.21, p=0.38) in YCE and CE respectively. Physical(p=0.043) and emotional function (0.017), fatigue (p=0.002), pain (p=0.031), appetite loss (< 0.001) arm symptoms (0.035) and systemic therapy side effects (0.036) reduced at 6-9mo in YCE, with sustained improvements in physical (p=0.036) and emotional function (p=0.008) at 54mo. The median score of fatigue after adjuvant therapy measured by QLQ C30 was lower in YCE compared to CE (11.11vs 22.22, p = 0.002). Similarly, in BFI the baseline median scores of severity of fatigue were 5 in YCE and 6 in CE which reduced to 3 at one year in both groups. A further reduction to 0 was observed in the YCE arm at 2 years and then sustained till 4 years compared to the median score of fatigue in CE which stayed at 3. (p=0.04, 0.03 2 and 4 years respectively). In VPS the number of patients experiencing severe pain in YCE group were less than CE group with specific reduction noted in pain over the breast/chest wall (p=0.018 at 24mo). Lastly SQ assessed spirituality and showed no difference, but less deterioration compared to baseline scores were noted in YCE. Fifty-three percent women on YCE showed an improvement in QOL from baseline compared to 47% in CE, however the global score of QOL did not differ significantly between the two arms. This cohort had overall compliance of 61% to yoga and physiotherapy in YCE with 91.75% compliance among those who did yoga for 6-9mo and 85% to physiotherapy alone in CE. Conclusions: Yoga resulted in a 15% relative improvement in DFS and 14% in OS, that did not reach statistical significance in this trial. Yoga is a low-risk, low-cost therapy that improves day-to-day activity, including pain, fatigue and quality of life in women with breast cancer.This is the first study where the long term benefits in quality of life have been noted with the addition of yoga for women undergoing treatment for breast cancer. Citation Format: Nita S. Nair, Nishu S. Goel, Vani Parmar, Ashwini Dewade, Shabina Siddique, Aarti Pandey, Rohini Hawaldar, Rajendra Badwe. The role of Yoga as a complementary therapy in women undergoing treatment for breast cancer: A randomized controlled trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD8-04.

DASL-HiCaP: A randomized, phase 3, double-blind trial of darolutamide with androgen-deprivation therapy and definitive or salvage radiation for localized very high-risk prostate cancer.

TPS396 Background: Radiation therapy (RT), plus androgen deprivation therapy (ADT) with a luteinizing hormone releasing hormone analogue (LHRHA), is a standard of care for patients with very high-risk localized prostate cancer (PC), or with very high-risk features and persistent PSA after radical prostatectomy (RP). Despite this, incurable distant metastases develop within 5 years in 15% of patients with very high-risk features. Darolutamide is a structurally distinct oral androgen receptor antagonist with low blood-brain-barrier penetration, a demonstrated favorable safety profile, and low potential for drug-drug interactions. Our aim is to determine the efficacy of adding darolutamide to ADT and RT used either as primary definitive therapy, or as salvage therapy, for very high-risk PC. Methods: This study is a randomized (1:1), phase 3, placebo-controlled, double-blind, international trial for patients planned for RT who have very high-risk localized PC on conventional imaging; or very high-risk features with PSA persistence or rise within one year following RP. The trial is stratified by previous RP; planned use of adjuvant docetaxel; clinical or pathological pelvic nodal involvement. 1100 participants will be randomized to receive darolutamide 600 mg or placebo twice daily for 96 weeks in combination with SOC (LHRHA for 96 weeks, plus RT starting week 8-24 from randomization). Participants are allowed nonsteroidal antiandrogen in addition to LHRHA for up to 90 days prior to randomization. Early treatment with up to 6 cycles of docetaxel completed at least 4 weeks prior to RT is permitted. The primary endpoint is metastasis-free survival, with secondary endpoints of overall survival, PC-specific survival, PSA-progression free survival, time to subsequent hormonal therapy, time to castration-resistance, frequency and severity of adverse events, health related quality of life, fear of recurrence. Tertiary endpoints include incremental cost-effectiveness, and identification of prognostic and/or predictive biomarkers of treatment response, safety, and resistance to study treatment. Clinical trial information: NCT04136353 .

123P IMpower010: Exploratory overall survival (OS) with adjuvant atezolizumab (atezo) vs best supportive care (BSC) in stage II-IIIA NSCLC with high PD-L1 expression

IMpower010 (NCT02486718) showed a statistically significant benefit in primary-endpoint disease-free survival (DFS) with adjuvant atezo vs BSC in resected stage II-IIIA PD-L1 tumour cell (TC) ≥1% (SP263) NSCLC after platinum-based chemotherapy. This finding led to the approval of atezo in this setting in the US, China, Japan and other countries and to its approval for stage II-IIIA PD-L1 TC ≥50% NSCLC in the EU and other countries. At the first pre-specified interim analysis (IA) of OS (cutoff 18 Apr 2022), the secondary endpoint of OS in the ITT population was not mature, but OS is of clinical interest in this curative setting; in pts with stage II-IIIA and stage II-IIIA PD-L1 ≥1% NSCLC, the respective OS HRs were 0.95 (95% CI: 0.74, 1.24) and 0.71 (95% CI: 0.49, 1.03) (Wakelee JTO 2022; 17:S2).

The Impact of Social Vulnerability Index on Survival Following ASCT for Multiple Myeloma

Background: The prognosis of patients with multiple myeloma (MM) has significantly improved with the advancement of highly effective therapies. High dose chemotherapy with an autologous hematopoietic stem cell transplant (ASCT) continues to be the standard of care for eligible patients with MM. While several factors affect survival following ASCT, the impact of social determinants of health, especially the local level social vulnerability, on survival in this patient population is not well documented. This study will use the CDC Social Vulnerability Index (SVI) to capture local levels of social vulnerability. Composed of 15 social factors, SVI is a constantly evolving measure of a community's ability to respond to hazardous events and helps public health officials identify populations in most need of support. SVI has traditionally been used for natural disaster outreach, but recently has been studied in cancer patients. These social factors are grouped into four related themes (socioeconomic status, household composition and disability, minority status and language, and housing type and transportation), which comprise a community's overall vulnerability ranking. The areas with higher levels of SVI are at a higher risk during public health emergencies. Aim: This study evaluated the impact of SVI and other social determinants of health on progression free survival (PFS) following an ASCT. Methods: A retrospective analysis of patients who underwent an ASCT in a single center from 2012 to 2020 was conducted. Patients were followed from time of diagnosis to 5 years post-transplant, if applicable. Socioeconomic data was obtained using the transplant center's database, the 2003 rural-urban continuum codes provided by US Department of Agriculture, and the CDC SVI, which uses census statistical data to identify the most vulnerable populations. Variables examined included age, gender, race, primary insurance payor, geographic location (urban/rural), and SVI, with a higher SVI implying a greater level of vulnerability among the county. Logistic regression analysis was performed to determine the odds ratios (OR) for the primary endpoint of PFS and for the secondary endpoint of overall survival (OS), while controlling for characteristics. Logistic regression using both full set of control variables and stepwise selection method were used to identify key predictors of PFS and OS. Results: 225 consecutive patients with MM who received ASCT participated, with the majority having been transplanted in the last 5 years. 151 (67%) achieved PFS at 5 years post-transplant and 171 (76%) remained alive at 5 years post-transplant. 209 (93%) patients received post-transplant maintenance therapy, and 77 (34%) had high-risk cytogenetics according to mSMART 3.0 criteria. The majority (72%) of the study population were Non-Hispanic White and most patients (60%) had public insurance payors. Race, insurance payor, or living in urban/rural areas did not affect PFS or OS. 53 (24%) patients lived in high SVI areas (SVI above median of SVI distribution). Treating SVI as a continuous value from 0 to 1, as the CDC scores SVI, we found that higher SVI values were significantly associated with lower odds of PFS post-transplant (OR=0.347, p<0.05). Patients living in higher SVI communities also saw a trend toward lower OS (OR=0.321) post-transplant (p<0.10). Of patients living in high SVI areas, only high-risk cytogenetics were significantly associated with lower odds of PFS (OR=0.0693, p<0.01) and OS (OR=0.294, p<0.05). Conclusion: Data from this single center retrospective study demonstrated that a higher SVI was associated with a lower PFS, while race, insurance payor, and urban/rural location had no significant association with PFS. This suggests that areas with high SVI may need more resources to achieve optimal PFS. Future studies will focus on efforts to address the factors in SVI, so all patients have opportunities for excellent outcomes after ASCT for MM. Factors that may be prudent to concentrate on include transportation, housing, and employment, as these components may be more easily intervened upon in future studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patterns of Care and Data Quality in a National Registry of Black and White Patients with Merkel Cell Carcinoma.

Simple SummaryMerkel Cell Carcinoma is a rare skin cancer most commonly affecting White patients. Less is known for Black patients. We aimed to report presentation, treatment, and quality of registry data by race with a secondary endpoint of overall survival. Findings from this work aim to impact patient and provider awareness to further equitable access to optimal cancer care across the spectrum from diagnosis and treatment to post-therapy surveillance for patients with Merkel Cell Carcinoma.Merkel Cell Carcinoma (MCC) is a rare cancer most commonly affecting White patients; less is known for Black patients. We aim to report presentation, treatment, and quality of registry data by race with a secondary endpoint of overall survival. We conducted a retrospective cohort analysis between 2006–2017 via the National Cancer Database of Black and White MCC patients with and without known staging information. Multivariable logistic, proportional odds logistic, and baseline category logistic regression models were used for our primary endpoint. Multivariable Cox regression was used to interrogate overall survival. Multiple imputation was used to mitigate missing data bias. 34,503 patients with MCC were included (2566 Black patients). Black patients were younger (median age 52 vs. 72, p < 0.0001), had higher rates of immunosuppression (28% vs. 14%, p = 0.0062), and were more likely to be diagnosed at a higher stage (proportional OR = 1.41, 95% CI 1.25–1.59). No differences were noted by race across receipt of definitive resection (DR), though Black patients did have longer time from diagnosis to DR. Black patients were less likely to receive adjuvant radiation. Black patients were more likely to have missing cancer stage (OR = 1.69, CI 1.52–1.88). Black patients had decreased adjusted risk of mortality (HR 0.73, 0.65–0.81). Given the importance of registry analyses for rare cancers, efforts are needed to ensure complete data coding. Paramount to ensuring equitable access to optimal care for all is the recognition that MCC can occur in Black patients.