Progression-free Survival Estimates Research Articles

A preliminary investigation of the relationship between 18F-FDG PET/CT metabolic parameters and prognosis in angioimmunoblastic T-cell lymphoma.

The goal of the study was to determine the prognostic significance of metabolic parameters in baseline 18F-FDG PET/CT images obtained from patients with angioimmunoblastic T-cell lymphoma (AITL). Forty patients with pathologically diagnosed AITL who had baseline 18F-FDG PET/CT between May 2014 and May 2021 were assessed as part of this study. Maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and total metabolic tumor volume (TMTV) were obtained and analyzed. In addition, many relevant features were evaluated, including sex, age, staging, International Prognostic Index (IPI), prediction index for T-cell lymphoma (PIT), Ki-67, and so on. Estimates of progression-free survival (PFS) and overall survival (OS) were determined using the log-rank test and Kaplan-Meier. The median follow-up was 30.2 months (interquartile range 9.82-43.03). Throughout the follow-up period, 29 (72.5%) deaths occurred and 22 (55.0%) patients made progress. The rates for 2- and 3-year PFS were 43.6% and 26.4%, respectively. The 3- and 5-year OS were 42.6% and 21.5%. For TMTV, TLG, and SUVmax, the cut-off values were 87.0 cm3, 711.1, and 15.8, respectively. Poorer PFS and OS were substantially correlated with high SUVmax and TLG. An increased TMTV suggested a shorter OS. TLG performed independently as OS predictors in multivariate analysis. The risk score for predicting the prognosis of AITL includes the TMTV, TLG, SUVmax, and IPI scores, with 4.5 for TMTV, 2 for TLG, 1.5 for IPI scores, and 1 for SUVmax. Three risk categories of patients with AITL had 3-year OS rates of 100.0%, 43.3%, and 25.0%, respectively. Baseline TLG was a strong predictor of OS. Here a new prognostic scoring system for AITL based on the clinical indicators and PET/CT metabolic parameters was constructed, which might make stratification of prognosis easy and also help to individualize treatment.

Primary overall survival analysis of the phase 3 randomized ZUMA-7 study of axicabtagene ciloleucel versus standard-of-care therapy in relapsed/refractory large B-cell lymphoma.

LBA107 Background: In ZUMA-7 (NCT03391466), axicabtagene ciloleucel (axi-cel) was superior to standard of care (SOC; hazard ratio [HR], 0.398; P<.0001) in the primary analysis of event-free survival as second-line therapy in patients with early relapsed or refractory large B-cell lymphoma (R/R LBCL; Locke et al. NEJM. 2022). In a preplanned interim analysis, median overall survival (OS) was not reached in the axi-cel arm and was 25.7 mo in the SOC arm (HR, 0.71; 95% CI, 0.52-0.97; Locke et al. TCT 2022. Abstract 1). We now report the primary OS analysis of ZUMA-7. Methods: Study procedures and eligibility were previously reported. The intention-to-treat (ITT) primary OS analysis occurred 5 years after the first patient was randomized (01/25/2018) per protocol. A log-rank test stratified by randomization stratification factors compared OS between the 2 arms. In addition to the ITT analysis and to account for subsequent treatment with cellular immunotherapy off protocol in the SOC arm, prespecified sensitivity analyses of OS were conducted using the Rank-Preserving Structural Failure Time (RPSFT) and Inverse Probability of Censoring Weights (IPCW) models. Other endpoints included progression-free survival (PFS) per investigator assessment, OS in key subgroups, and safety. Results: In total, 359 patients were randomly assigned, 180 to axi-cel and 179 to SOC. As of 01/25/2023, at a median follow-up of 47.2 mo, axi-cel demonstrated a statistically significant improvement in OS over SOC (HR [95% CI], 0.726 [0.540-0.977]; stratified log-rank 1-sided P=0.0168 [efficacy boundary, 0.0249]). Median OS was longer with axi-cel vs SOC (not reached vs 31.1 mo, respectively); 48-mo OS estimates were higher with axi-cel (54.6% vs 46.0%, respectively). OS benefit with axi-cel vs SOC was consistent in prespecified key subgroups, including age ≥65 years, primary refractory, early relapse, high-grade B-cell lymphoma, and high second-line age-adjusted IPI. In the SOC arm, 102 (57%) patients received subsequent cellular immunotherapy off protocol. Prespecified OS sensitivity analyses, conducted to address the confounding effects of treatment-switching in the SOC arm, showed an even greater OS benefit with axi-cel vs SOC, with stratified HR (95% CI) of 0.608 (0.449-0.824) by RPSFT and 0.633 (0.409-0.981) by IPCW. PFS by investigator confirmed benefit of axi-cel over SOC (HR [95% CI], 0.506 [0.383-0.669]), with 48-mo PFS estimates of 41.8% vs 24.4%, respectively. No new cytokine release syndrome or neurologic events and no new treatment-related deaths occurred since the primary EFS analysis. The safety profile of axi-cel remained consistent with prior studies. Conclusions: Axi-cel as second-line therapy demonstrated a significant improvement in overall survival over historical standard of care in patients with early relapsed/refractory LBCL. Clinical trial information: NCT03391466 .

Outcomes with bendamustine lymphodepletion prior to brexucabtagene autoleucel for mantle cell lymphoma.

e19540 Background: Brexucabtagene autoleucel (brexu-cel) is approved for relapsed/refractory mantle cell lymphoma (MCL). Cyclophosphamide/fludarabine for lymphodepletion (LD) is standard LD prior to brexu-cel. Due to a recent fludarabine shortage as well as institutional practice, we have utilized alternatives to fludarabine-based LD prior to brexu-cel, predominantly bendamustine. Bendamustine is an attractive option because it is included in the label for another anti-CD19 CAR T cell product. We report our institutional experience with bendamustine LD followed by brexu-cel. Methods: We retrospectively examined our institutional records for all patients with MCL who were treated with bendamustine LD followed by brexu-cel from 2020-2022. Progression-free survival (PFS) was analyzed with Kapalan-Meier survival analysis. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria. Results: 16 patients received bendamustine followed by brexu-cel. Median age was 65 years (range: 54-76). Median number of prior therapies was 3 (range: 3-8). All patients (100%) had received a BTK inhibitor prior to brexu-cel. 14/16 (88%) received bridging therapy. 14/16 (88%) patients had CRS; 11/14 (79%) had grade 1-2 CRS and 3 (21%) had grade 3 or greater CRS. 5 (31%) patients had ICANS; 2 (40%) had grade 1-2 ICANS, and 3 (60%) had grade 3 or greater ICANS. 10 (63%) patients received tocilizumab, 8 (50%) received dexamethasone, and 3 (19%) received anakinra for management of CRS and/or ICANS. Best objective response rate (ORR) was 81% with 11 (69%) patients achieving CR. Median follow-up was 13.4 months. Estimated 6-month progression-free survival was 86% (95%CI: 54-96%) and 12-month progression-free survival was 63% (95%CI: 32-82). Conclusions: Bendamustine LD prior to brexu-cel for MCL is feasible, and, although these numbers are small, appears to have comparable outcomes to that reported in real world brexu-cel data (best ORR 90% with 82% CR rate, 6 month PFS estimate 69%, 12 month PFS estimate 59%; Y Wang et al. J Clin Oncol 2023) and ZUMA-2 outcomes (93% ORR with 67% CR rate, 12 month PFS estimate 61%; M Wang et al. NEJM 2020).

Impact of imaging frequency on progression free survival in Alliance clinical trials enrolling patients with untreated follicular lymphoma.

7520 Background: With goal of simplifying clinical trials in lymphomas, we reported that bone marrow biopsies are irrelevant for response assessment in most patients (pts) with follicular lymphoma (FL) on trials (Rutherford JCO 2023). We then investigated impact of imaging frequency in FL clinical trials. We hypothesized that progression free survival (PFS) would not be different when imaging is performed less frequently than required by trials. Methods: We identified all trials through Alliance for Clinical Trials in Oncology that enrolled untreated pts with FL from 2008-2016. We considered 2 imaging schedules: protocol specified (control) vs relaxed (X) in which response assessments at every other required time point were omitted. For each trial, we estimated PFS using Kaplan Meier methods for the 2 schedules then determined difference in PFS between schedules as % change from control schedule in 2 year (yr) PFS rate. We performed simulation studies to approximate impact of less frequent imaging on PFS estimation using 50901 (low-intermediate risk FL) and 50904 (intermediate-high risk FL, control arm). We assumed exponential distribution for PFS, where rate parameter was calculated based on observed median PFS with uniform censoring distribution. Protocols for 50901 and 50904 mandated imaging every 4 months (mos) for 2 yrs then every 6 mos (S0). We ran 1000 iterations of 100 observations using 3 tumor assessment follow up schedules: every 6 mos for 2 yrs then yearly (S1), every 8 mos for 2 yrs then yearly (S2), or yearly (S3) for simulated progression times. We calculated deviation of PFS using simulated schedules from truth (S0). Results: Across 5 FL trials, median percent change of schedule X from control schedule in estimated 2yr PFS was 2.1% (0.0-30.8%) and in estimated 4yr PFS was 0.9% (-8.6-25.7%). Disparate result in 50901 is due to small shift in events with low number of pts at risk for progression. Simulation study results by trial were: for 50901, true median PFS 1.9 yrs and average median PFS for S1, S2, and S3 of 2.05, 2.11, and 2.21 yrs; for 50904 (control arm), true median PFS 4.1 yrs and average median PFS for S1, S2, and S3 of 4.16, 4.12, and 4.05 yrs. Conclusions: Our findings support decreased frequency of imaging studies in FL clinical trials, which would improve resource use and decrease pt burden. We plan a larger analysis to confirm results. https://acknowledgments.alliancefound.org . Clinical trial information: NCT00553501 , NCT01145495 , NCT01190449 , NCT01286272 , NCT01829568 .[Table: see text]

Sequential use of antibody-drug conjugate after antibody-drug conjugate for patients with metastatic breast cancer: ADC after ADC (A3) study.

1022 Background: Optimizing sequential use of Antibody Drug Conjugates (ADCs) is an area of unmet need and of rising clinical importance. With the recent approvals of sacituzumab govitecan (SG) for HR+/HER2- and triple negative metastatic breast cancer (MBC) as well as trastuzumab deruxtecan (T-DXd) for HER2-low MBC, many patients are now candidates for multiple ADCs. However, given potential cross-resistance based on antibody target vs payload (Coates et al, Cancer Discov. 2021), optimal sequencing remains uncertain. We evaluated the safety and efficacy of ADC after ADC for patients with HER2 negative MBC. Methods: We included all patients at an academic institution treated with more than one ADC for MBC. Each line of ADC beyond the first was evaluated for presence of the same “antibody target” or “payload” compared to prior ADC. Clinicopathological information was gathered by chart review. We defined “cross-resistance” as progressive disease (PD) at time of first restaging on second ADC. Progression-free survival (PFS) was evaluated as time from start of treatment to disease progression or death from any cause. All PFS estimation was done using the KM method. All pairwise comparisons across ADC were done using a Wilcoxon Rank Sum test to allow for divergences from normality in progression times. Significance was declared as a type I error less than 0.05. Results: A total of 193 patients with MBC were treated with ADCs between August 2014-February 2023. Among these,32 patients were identified as having received more than one ADC (HR+/HER2- = 13, TNBC = 19, HER2 low = 22). Median age at time of second ADC was 57.1 years (range 31.3-88.6) and patients had received a median of 4 lines (range 2-12) of prior treatment before initiation of second ADC. The median PFS on the first ADC used (ADC1) was significantly longer at 7.55 months (95% CI 3.22-10.25) compared to a median of 2.53 months on the second ADC (ADC2) (95% CI 1.38-4.14) (p=0.006). PFS for ADC2 with antibody target change was 3.25 months (95% CI 1.38 months, n/a) compared to 2.30 months with no target change (95% CI 1.38 months, n/a) (p=0.16). At time of first imaging, cross-resistance was present in 17 cases (53.1%), absent in 12 (37.5%), and not evaluable in 3 cases. When the second ADC contained the same antibody target as the first, cross-resistance was present in 9/13 cases (69.2%), compared to 8/16 cases (50.0%) when the second ADC targeted a different tumor antigen. Similarly, differences were noted based on payload switch vs not. Conclusions: This study highlights a subset that had cross-resistance to ADC after ADC, while others had durable responses on latter lines of therapy, particularly if a different antibody target was utilized. Further research is needed to validate these findings and discern mechanisms of clinical resistance to guide optimal sequencing of ADC-based treatment options.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy. Nearly one-third of patients are >75 y, and advanced age is an adverse prognostic variable. R-miniCHOP, a dose attenuated version of standard R-CHOP, offers a 2-year progression-free survival (PFS) of 47% based on phase II data (Peyrade F et al, 2011). For comparison, patients age 60-80 have about a 75% 2-year overall survival (OS) with R-CHOP chemotherapy (Coiffier B et al., 2002). A key dilemma is identifying which older patients with DLBCL should be considered for curative intent chemoimmunotherapy. The FIL (Fondazione Italiana Linfomi; Italian Lymphoma Foundation) has developed a tool accounting for age, comorbidities, and ability to perform daily and instrumental activities to classify patients as fit, unfit, or frail (Tucci A et al, 2015), with a key observation being improved survival when curative intent chemoimmunotherapy was delivered to fit and unfit patients. (Merli F et al., 2021). However, there is no prospective validation of frailty assessment and treatment outcomes. Epigenetic deregulation is a feature of DLBCL in older patients. Pre-clinical models show that pre-treatment with hypomethylating agents improves the anti-tumor effect of the agents contained in R-CHOP (Clozel T et al., 2013). Early studies of azacitidine with R-CHOP showed promising efficacy and acceptable toxicity (Martin P et al., 2022). The availability of oral azacitidine is appealing, reduces the infusion burden of treatment, and is agnostic to cell-of-origin. Methods: S1918 is a randomized trial of R-miniCHOP ± oral azacitidine in patients >75 y with newly diagnosed aggressive B-cell non Hodgkin lymphomas (NCT04799275). This is the first randomized study in this population conducted in North America by the National Clinical Trials Network (NCTN) and will enroll 384 patients. Patients receive prephase therapy with prednisone 60–100 mg × 4–7 days to improve performance status and decrease early treatment-related mortality (Owens CN et al., 2015; Pfreundschuh M et al., 2008). A safety run-in has been completed. The phase II objective is to determine if oral azacitidine + R-miniCHOP should be tested further against R-miniCHOP based on estimates of 1-year PFS. The phase III objective is to compare OS at 2 years between arms. S1918 incorporates the FIL Tool for baseline frailty assessment and a serial comprehensive geriatric assessment to evaluate effects of therapy on quality of life and functional status. Key correlative tests include circulating tumor DNA (ctDNA) assays to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has potential to impact future trial design and change the standard of care for patients > 75 y with aggressive lymphoma with its randomized design, incorporation of baseline frailty and geriatric assessments, and utilization of ctDNA correlatives. The research was funded by: NIH/NCI grants U10CA180888, U10CA180819, U10CA180820, and U10CA180821; and in part by Celgene Corporation (now part of Bristol-Myers Squibb). Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies, ongoing trials Conflicts of interests pertinent to the abstract. E. A. Brem Consultant or advisory role Bayer, TG Therapeutics, Astra Zeneca, BeiGene Honoraria: Astra Zeneca, BeiGene, SeaGen, Morphosys/Incyte, Pharmacyclics/Janssen P. Caimi Research funding: Abbvie, ADC Therapeutics, Genentech, Consultancy: Abbvie, ADC Therapeutics, Beigene, BMS, Genentech, Incyte, Kite, Lilly, MEI Pharma, Novartis, Takeda R. L. Olin Consultant or advisory role Actinium, Servier Research funding: Cellectis B. Kahl Consultant or advisory role Genentech, BMS J. P. Leonard Consultant or advisory role Roche/Genentech, BMS/Celgene

Autologous and allogeneic stem‐cell transplantation for transformed Waldenström macroglobulinemia

Introduction: The prognosis of histological transformation (HT) in Waldenström macroglobulinemia (WM) is unfavourable despite the use of diffuse large B-cell lymphoma-directed chemo-immunotherapy. The aim of this study was to evaluate the outcomes after autologous stem-cell transplantation (autoSCT) or allogeneic stem-cell transplantation (alloSCT) in patients with transformed WM. Methods: Patients who received autoSCT or alloSCT between January 1996 and December 2021 were identified in an international multicenter database of 285 patients with transformed WM. The primary end-point was overall survival (OS), calculated from the date of SCT to death from any cause. Secondary end-points were progression-free survival (PFS), incidence of relapse/progression and non-relapse mortality (NRM). Univariate and multivariate analyses were performed using the Cox proportional hazards model for OS and PFS only for the autoSCT cohort, due to the small sample size of the alloSCT cohort. Results: Fifty-six patients were included, 46 had received autoSCT and 10 alloSCT. The median time from HT diagnosis to SCT was 8 months (range, 2–76 months) for autoSCT and 7 months (range, 3–49 months) for alloSCT. The patients received a median of 2 lines of treatment for HT before SCT (range, 1 to 6 for autoSCT and 1 to 3 for alloSCT), and 89% (complete response (CR): 59%) and 80% (CR: 50%) of the patients had chemosensitive disease at the time of autoSCT and alloSCT, respectively. For autoSCT, the conditioning regimen was BEAM in 76% of the patients, and for alloSCT, reduced-intensity conditioning was used in 70% of the cases. The median follow-up time for the surviving patients was 5.5 years (95% CI, 2.8–7.1 years) from autoSCT and 12.6 years (95% CI, 2.7–14.4 years) from alloSCT. The 3-year estimates of OS, PFS and cumulative incidences of relapse and NRM were 57%, 44%, 54%, and 2% for autoSCT and 50%, 50%, 30%, and 20% for alloSCT, respectively. In the autoSCT cohort, CR at SCT was found to be associated with superior OS and PFS (3-year OS, 81% for CR vs. 23% for less than CR, P = 0.001 and 3-year PFS, 62% vs. 21%, P < 0.001) and less than 2 lines of therapy for HT with superior OS (3-year OS, 75% for 1 line vs. 36% for >1 line, P = 0.01). Keywords: Aggressive B-cell non-Hodgkin lymphoma, Stem Cell Transplant No conflicts of interests pertinent to the abstract.

Long-term outcome for patients with advanced non‒small-cell lung cancer treated by autologous cytokine-induced killer (CIK) cell immunotherapy in combination with sintilimab plus chemotherapy: NSCLC-CCICC-002.

9096 Background: Autologous cytokine-induced killer (CIK) cell immunotherapy in combination with Sintilimab demonstrated robust antitumor activity and safety in the phase Ib CCICC-002 study (NCT03987867) of Non‒Small-Cell Lung Cancer. Long-term outcomes in patients are reported herein. Methods: Systemic therapy naïve patients received platinum-based doublet chemotherapy, Sintilimab (PD1 inhibiter), and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or two years. Kaplan-Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were based on immune-related response criteria by investigator assessment (data cut-off, January 31, 2023). Results: From May 2019 to Jan 2021, CCICC-002 enrolled 33 patients（19 squamous, 14 non-squamous NCSLC; 1 patient was excluded because the second biopsy revealed EGFR mutation) aged 46-73 years with median follow-up was 31.4 months (range, 7.6-44.4 months). Estimated 3-year OS was 51.8% in all patients; median OS was not reached (95% CI, 26.6 months-not reached) in all patients. In subgroups, median OS was 27.6 months (95% CI, 13.4 months-not reached) in squamous NCSLC and not reached (95% CI, 29.9 months-not reached) in non-squamous NCSLC, respectively. Median OS was not reached (95% CI, 27.6 months-not reached) in PD-L1 positive patients and 28.3 months (95% CI, 15.6 months-not reached) in PD-L1 negative patients, respectively. Estimated 3-year PFS rate was 27.5% and median PFS was 17.9 months (95% CI, 8.2-26.5 months) in all patients. Median PFS was 17.3 months (95% CI, 5.0-24.0 months) in squamous NCSLC and 22.4 months (95% CI, 5.7 months-not reached) in non-squamous NCSLC, respectively. Median response duration was 18.7 months (95% CI, 10.1-27.6 months). 30.3% of patients were ongoing at data cut-off, and the longest response was ongoing at 41.3 months. 1 of the 5 CMR (complete metabolic response by PET-CT) patients experienced disease progression during observation. Treatment-related AEs (TRAEs) occurred in 94.0% of patients and resulted in study discontinuation in 7.8%, and 15.2% experienced grade 3/4 TRAE. Conclusions: This long-term analysis of CCICC-002 represents the longest follow-up for CIK to date and confirms the durable antitumor activity and tolerability of CIK cells therapy in combination with Sintilimab plus chemotherapy in advanced NCSLC. Further studies are warranted to confirm these preliminary results. Clinical trial information: NCT03987867 .

Dose expansion results of the bifunctional EGFR/TGFβ inhibitor BCA101 with pembrolizumab in patients with recurrent, metastatic head and neck squamous cell carcinoma.

6005 Background: Pembrolizumab (P) is approved to treat patients (pts) with recurrent, metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). BCA101 is a first-in-class bifunctional EGFR antibody fused to a TGFβ immune modulating payload which is well tolerated and has clinical activity as monotherapy and in combination with pembrolizumab in advanced solid tumors (ESMO 2022 731MO). Here we report the results from the interim analysis of an expansion cohort combining BCA101+P as first line therapy in R/M HNSCC. Methods: This ongoing single-arm, open-label multicenter dose expansion cohort enrolled pts with R/M HNSCC with a tumor PD-L1 CPS≥1 with no prior systemic therapy for R/M disease, ECOG 0-1, and measurable disease (RECIST v1.1). Pts received BCA101 (1500 mg IV on days 1, 8, 15) with P (200 mg IV on day 1) every 21-days. Primary endpoint: safety; secondary endpoints: overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS). Exploratory: molecular and immunologic predictors of response. A Simon optimal two-stage design was employed: among 18 evaluable pts in stage 1, &gt;3 pts in response triggered continuation to stage 2 enrolling 21 additional pts targeting an ORR&gt;35%. Results: From 2/2022 to 1/2023, 20 pts enrolled while 18 were evaluable (had first restaging scans) in stage 1. Pts were more often men (n=13, 65%) with a median age of 66 (range: 31-77). Oropharynx (10, 50%) [7/10 (70%) were HPV/p16-pos] and oral cavity (7, 35%) were the most common primary subsites (larynx/hypopharynx: 3). Fifteen (75%) had distant metastatic disease. The ORR in stage 1 was 44% (8 PRs, 4 SD) with a clinical benefit rate (CBR=PR+SD) of 67%; 7/12 (58%) HPV-neg pts achieved a response. Median DOR not reached, but median time on-treatment was 6.7 months (range: 2.7-11.0+) among responders. Ten pts discontinued therapy; all but 1 for PD (n=1 for toxicity). Grade 3+ treatment-related adverse events (TRAEs) were observed in 4 pts (20%, most common: anemia). No treatment-related deaths were observed. Acneiform rash was the most common TRAE of any grade (15, 75%). PFS and OS estimates are forthcoming. Eight (44%) had baseline PD-L1 CPS scores of 0-19, while ten (56%) were ≥20. Stage 2 is actively enrolling with completion of accrual expected by the meeting. Conclusions: Stage 1 of this dose expansion cohort of BCA101+P shows encouraging anti-tumor activity with additive potential, particularly among HPV-neg pts; and the combination is well tolerated among this R/M HNSCC population. Further investigation is warranted. Study funded by Bicara Therapeutics and conducted in collaboration with Merck Sharp &amp; Dohme LLC, a subsidiary of Merck &amp; Co., Inc. USA (NCT04429542). Clinical trial information: NCT04429542 . [Table: see text]

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: In clinical trials, treatment of chronic lymphocytic leukemia (CLL) with venetoclax (Ven) has shown promising efficacy and good tolerability.1,2 However, patients treated in clinical trial are often not representative in daily practice. Prospective real-world data on Ven usage are limited. Objective: We conduct a prospective non-interventional observational study assessing effectiveness, safety, and quality of life in relapsed/refractory patients (RR) treated with Ven in Austria, Germany, and Switzerland. The population enrolled is representative for patients treated with Ven according to local label.3 This report focuses on patients treated with Ven in combination with rituximab (R). Methods: Adult patients with CLL requiring therapy treated with Ven+R according to local label are eligible for the study. Patient’s visits are scheduled at the physician’s discretion and according to clinical practice. Study documentation is possible at baseline, weekly during ramp-up, monthly until the end of 6 months and 3-monthly afterwards up to a maximum of 3 years. Response assessment according to iwCLL criteria can be documented at the end of ramp-up, after 3, 12, and 24 months. Results: Until Nov 4th, 2022, 106 patients receiving VenR were enrolled, 105 with at least one dose of Ven (= safety population), for 87 treatment response had been documented at least once (= effectiveness population). Median age at therapy start was 74 years, 72.6% of patients were male, 76.4% had at least one comorbidity, most commonly cardiovascular (57.5%) and 73.6% received comedication. Patients were pre-treated with a median of 1 (range 1-10) line of therapy, e.g., chemo-immuno-therapy (CIT: 75.5%) or B-cell receptor inhibitors (34.9%). Del(17p), TP53 mutation, and presence of unmutated IGHV had been diagnosed in 23.6%, 24.5%, and 40.6%, respectively (excl. missing data: 28.7%, 30.6%, 69.4%). With a median observation time of 652 (range 14-1364) days, 93.3% of patients experienced at least one AE, 58.1% experienced CTCAE grade 3/4 AEs, SAEs were reported in 41.0%. Grade 5 AEs were reported in 10 patients, tumor lysis syndrome (TLS) in 12 patients (11.4%). The median for progression-free survival (PFS) and overall survival (OS) has not been reached, the 24-month estimates were 80.1% (PFS) and 84.1% (OS). The reported best overall response at 24 months was 88.5% (CR+CRi 59.8%; PR: 28.7%). Remissions continue to deepen with longer treatment duration. Conclusions: Under real-world conditions, VenR is used in elderly patients with comorbidities. The treatment was well tolerated. Most patients receive VenR in 2L of therapy after initial CIT. The response rate in patients presenting with high risk features, e.g., del(17p), TP53 mutation or unmutated IGHV, was high. Despite the advanced age of the enrolled patient population, PFS and OS estimates are comparable to pivotal phase III trial MURANO. The research was funded by: AbbVie sponsored this study and contributed to the design, study conduct. Keywords: molecular targeted therapies, ongoing trials Conflicts of interests pertinent to the abstract I. Schwaner Consultant or advisory role AbbVie, Amgen, AstraZeneca, BeiGene, Janssen, Roche, Servier. H. Hebart Consultant or advisory role AbbVie, AstraZeneca, BeiGene, Celgene, Janssen, and Roche C. Losem Consultant or advisory role AbbVie, Amgen T. Wolff Consultant or advisory role Novartis, Celgene, Roche, Bayer, Teva and Abbvie B. Schmidt Consultant or advisory role AbbVie, Incyte, Celgene, Novartis, Roche, Hexal, Biotest, Bristol-Myers Squibb, Daiichi-Sankyo, Janssen und Amgen D. Rossi Consultant or advisory role AbbVie, AstraZeneca, Gilead, Janssen, Verastem, Roche, Cellestia C. Lehmann Employment or leadership position: employees of AbbVie and may own AbbVie stock J. Benzel Employment or leadership position: employees of AbbVie and may own AbbVie stock J. Huelsenbeck Employment or leadership position: employees of AbbVie and may own AbbVie stock P. Pichler Consultant or advisory role Amgen, Gilead, Janssen, Sanofi-Aventis, Takeda

Primary analysis of STARTAR: A phase 2 salvage trial of androgen receptor (AR) inhibition with androgen deprivation therapy (ADT) and apalutamide with radiation therapy (RT) followed by docetaxel in men with PSA recurrent prostate cancer (PC) after radical prostatectomy (RP).

5016 Background: ADT with salvage RT improves survival for men with PSA recurrence after RP. For high risk PSA recurrence, current standard ADT duration is up to 2 years with RT; shortening but intensifying systemic therapy may improve outcomes. The STREAM trial showed 6 mo enzalutamide with ADT/RT had 3-year progression free survival (PFS) of 53% in a high risk population, including lymph node (LN) positive. Given docetaxel (doce) improves survival in mHSPC, we evaluated the combination of salvage RT, ADT/apalutamide (apa) and doce in this setting. Methods: STARTAR is a multicenter investigator initiated phase 2 trial for salvage treatment of PSA recurrent PC post-RP, conducted in the DOD Prostate Cancer Clinical Trials Consortium. Key inclusion criteria included Gleason 7 with T3/positive margin/N1 or Gleason 8-10 PC, PSA relapse &lt;4 years post-RP (inclusion PSA 0.2-4 ng/mL), and &lt;4 positive LNs, standard imaging negative. Patients (pts) received ADT with apa for 9 months, RT (66-74 Gy to the prostate bed +/- pelvic LNs over 6-8 wks) starting wk 8, and then completed 6 cycles of concurrent doce 75mg/m2 q3 wks. The primary endpoint was 36 month PFS, defined as composite of freedom from PSA&gt;0.2 + post-RT nadir with subsequent rise, clinical progression, other therapy start, or death, among pts with testosterone (T) recovery (&gt;100ng/dL). Kaplan-Meier estimates for PFS were used to determine landmark 24 mo and 36 mo rates and compared to PFS rates from prior trials using a binomial test. Results: From 3/2018 to 2/2020, 39 pts were enrolled. As of 12/2022 data cutoff, median follow up was 36 months. Baseline characteristics: Gleason 7 in 54%; Gleason 8-10 in 46%; 23% LN positive; median PSA 0.58 ng/mL (range 0.21-3.40), and median time from RP 7.6 mo (range 2-98). 37 pts (95%) and 23 pts (62%) completed at least 1 and all 6 cycles doce, respectively. All pts achieved undetectable PSA nadirs. At 24mo and 36mo, PFS rates were 84% and 72%, respectively, with 95% pts recovering T at 36 mo. Compared to 40% historical PFS and 53% STREAM PFS rates, the 72% 36-mo PFS rate was statistically significantly improved (p&lt;0.001 and p=0.013, respectively). Common any-grade adverse events (AEs) included 98% hot flashes, 88% fatigue, 77% alopecia, 57% dysgeusia, and 53% rash (28% grade 1; 15% grade 2, 10% grade 3), with 5% febrile neutropenia. Conclusions: In this first phase 2 trial of ADT, apa, salvage RT, and 6 cycles of doce for high risk PSA recurrence, the primary endpoint 3-year PFS rate improved to 72%, indicating durable remissions beyond historic controls. Intensifying systemic treatments in the non-metastatic hormone sensitive but high risk salvage setting may be feasible and efficacious, with fewer pts experiencing cancer progression over time. Clinical trial information: NCT03311555 .

Long-term outcomes of PD-1 blockade in metastatic or unresectable cutaneous squamous cell cancer.

e21551 Background: Cutaneous squamous cell carcinoma (CSCC) is the 2nd most common malignancy in the US. Approximately 10% of patients will experience either recurrent or metastatic disease, leading to worsened morbidity and mortality. In 2019, anti-PD1 therapy was FDA approved for metastatic or unresectable CSCC, and has been established as the standard frontline systemic therapy for this disease. Here we present our long-term, follow-up data investigating the efficacy, safety, and durability of PD-1 therapy for CSCC. Methods: This is a retrospective cohort study of metastatic or unresectable CSCC patients treated with PD-1 therapy at the University of Southern California Norris Comprehensive Cancer Center and the Scripps MD Anderson Cancer Center between June 2016 and January 2023. Patient demographics, tumor characteristics, and treatment related variables were collected. Objective response (ORR) was collected per RECIST criteria. Kaplan-Meier curves were used to estimate progression free survival (PFS) and overall survival (OS). For patients receiving salvage therapy post-PD1, progression free survival 2 (PFS2) and objective response rate 2 (ORR2) were also calculated. Toxicities were graded per CTCAE v5.0. Results: A total of 39 patients diagnosed with CSCC received at least one cycle of PD-1 therapy; among these 8 were excluded from efficacy analysis. Patients were on average 68 years old (range 22-97), predominantly male (69.2%) and Caucasian (74.4%). The most common primary tumor location was head/neck (64.1%), followed by extremity (15.4%). The mean tumor diameter was 6.0 cm (4.5-7.5, 95% CI). The majority of tumors were either moderately (33.3%) or poorly (28.2%) differentiated. The most common sites of metastatic disease included lymph node (41.0%), skin/soft tissue (33.3%) and bone (25.6%). Patients received on average 7 cycles of PD-1 therapy (range 1-26) and were followed for median 13.8 months. ORR for all patients was 39.0%, including CR and PR in 7 (22.6%) and 4 (13.0%) patients, respectively; 10 patients (32.2%) achieved stable disease (SD), while 7 patients (22.6%) had progression of disease (PD). Median PFS was 6.8 months, while OS was 26.7 months. Among 10 patients receiving salvage therapy after PD-1, 6 (60.0%) received a platinum-containing regimen. Median PFS2 was 4.4 months, while ORR2 was 10.0% with 1 PR, 4 SD, and 5 with PD. PD-1 therapy was well tolerated with 13 patients (33.3%) experiencing Grade 1-2 toxicity and 2 patients (5.2%) experiencing Grade 3-4. Conclusions: In this study of long-term outcomes of CSCC patients treated with PD-1 blockade, we found that initial responses to PD-1 therapy were durable, although PFS2 was less durable for patients who required salvage therapy and ORR2 was low. Novel treatment options are needed for patients with advanced CSCC who do not achieve durable responses to PD-1 based therapy.

Real-world experience of checkpoint inhibitors across India: CRSF 2020-01.

e18862 Background: There are limited data available from India on the real-world use of checkpoint inhibitors. Hence we did this analysis across India to study the pattern of use and outcomes with checkpoint inhibitors. Methods: This was a retrospective multicentric protocol. Patients who received immunotherapy from January 2016 to October 2021 were included. The baseline demographic, previous treatment, response, date of progression, date of death and status were noted. SPSS version 20 was used for analysis. Descriptive statistics were performed. Kaplan Meier method was used for estimation of progression-free survival (PFS) and overall survival (OS). COX regression model was used to identify factors impacting OS. Results: We identified 308 patients in the study. The median age was 58.5 years (Interquartile range 51-66 years) and there was a male preponderance (249, 80.8%). The 3 commonest sites of use were head and neck cancer in 144 patients (46.8%), lung cancer in 81 (26.3%) and renal cell carcinoma in 31(10.1) patients. The ECOG PS was 0-1 in 215 (70%), 2 in 71 (23.1), 3-4 in 21(6.8%) and not documented in 1(0.3%) patient. The two most common checkpoint inhibitors used were nivolumab and pembrolizumab 255 (82.8%) and 37(12%) patients respectively. These were used in curative setting in 6 patients (1.9%) and palliative in rest all. 43(14%) patients received them as first-line in, 129 (41.9) as second-line and beyond the second line in 130 (42.2%) patients. The response rate was 24% (n = 74). The median PFS was 4.067 (95%CI 3.45-4.67) and the median OS was 10.0 months (95%CI 6.2-13.8). Among the factors tested for impact on OS the ECOG PS 0-1 ( HR-0.493 95%CI 0.324-0.749; P = 0.001), non head and neck site of the disease (HR-2.134 95%CI 1.164-3.911) and reception of immunotherapy in first line setting (HR -0.533 95%CI 0.295-0.963: P = 0.037) had an favorable impact on OS. Conclusions: Checkpoint inhibitors provide similar efficacy as those seen in pivotal studies in real-world settings.

OATH trial: A phase II clinical trial evaluating the combination of onapristone with anastrozole for women with hormone receptor positive endometrial cancer—Preliminary results.

5601 Background: Endometrial cancer is the most common gynecologic cancer and is primarily treated with chemotherapy. Many endometrial cancers though express hormone receptors and may respond to hormonal therapy, a potentially attractive non-chemotherapy alternative in such a population of women. The aim of OATH is to investigate the potential of dual hormonal blockade through the combination of antiprogesterone and anti-estrogen therapy via the administration of onapristone extended release (ONA) plus anastrozole (ANA), respectively. OATH is an open-label, multicenter, investigator-initiated, non-randomized, phase 2 study to evaluate the safety and efficacy of ONA + ANA in patients (pts) with endometrial cancer (EC). ClinicalTrials.gov Identifier: NCT04719273. Methods: Pts received ONA 50 mg twice daily plus ANA 1 mg once daily and were treated until progressive disease (PD) or unacceptable toxicity. Co-primary endpoints were 4-month progression-free survival (PFS) rate and overall response rate (ORR). A sample size of 25 pts will achieve 80% power to detect an improvement in 4-month PFS estimates from 25% (historical) to 52% and an improvement in response rate from 15% (historical) to 37%, using two-sided exact test at 5% significance level. Secondary endpoints include PFS, disease control rate (DCR), and safety. Results: As of January 20, 2023, 14 pts were enrolled. Median age was 67 years (44-80). ECOG performance status was 0 (36%), and 1 (64%). Number of prior chemotherapy regimens was 0 (1 pt,7%), 1 (9 pts, 64%) and 2 (4 pts, 29%). Seven (50%) pts received radiotherapy and 3 (21%) pts received prior checkpoint inhibitor therapy. Median treatment duration was 4.2 (1.0-19.9) months, and 8 pts remain on treatment. Adverse events were mainly grade 1 and 2. The most common treatment-related adverse events (AEs) and abnormal laboratory values were hot flashes (36%), alanine transferase (ALT) increased (29%), aspartate aminotransferase (AST) increased (29%), nausea (29%), and diarrhea (21%). No treatment-related serious AE, deaths on treatment, or treatment-related drug discontinuations were reported. The 4-month PFS Kaplan-Meier rate was 63.5%. Among 13 pts who had at least one tumor assessment after baseline, the best overall response was: 1 complete response, 1 partial response (response rate: 15.4%), 9 (69%) stable disease, and 2 (15.4%) progressions. Updated results will be presented. Conclusions: Preliminary results of dual hormonal blockade using ONA and ANA in heavily pretreated pts with EC suggest that this combination ONA + ANA has promising activity and is well tolerated. Clinical trial information: NCT04719273 .

PRIMARY OVERALL SURVIVAL ANALYSIS OF THE PHASE 3 RANDOMIZED ZUMA‐7 STUDY OF AXICABTAGENE CILOLEUCEL VERSUS STANDARD OF CARE IN RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA

PRIMARY OVERALL SURVIVAL ANALYSIS OF THE PHASE 3 RANDOMIZED ZUMA‐7 STUDY OF AXICABTAGENE CILOLEUCEL VERSUS STANDARD OF CARE IN RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA

The HI-FIVE Trial: A Prospective Trial Using 4-Dimensional 68Ga Ventilation-Perfusion Positron Emission Tomography-Computed Tomography for Functional Lung Avoidance in Locally Advanced Non-small Cell Lung Cancer

Functional lung avoidance (FLA) radiation therapy aims to spare regions of functional lung to reduce toxicity. We report the results of the first prospective trial of FLA using 4-dimensional gallium 68 ventilation-perfusion positron emission tomography-computed tomography (68Ga-4D-V/Q PET/CT). Inclusion criteria required a diagnosis of stage III non-small cell lung cancer and the ability to undergo radical-intent chemoradiation therapy. Functional volumes were generated using planning 68Ga-4D-V/Q PET/CT. These volumes were used to generate a clinical FLA plan to 60 Gy in 30 fractions. The primary tumor was boosted to 69 Gy. A comparison anatomic plan was generated for each patient. Feasibility was met if FLA plans (compared with anatomic plans) allowed (1) a reduction in functional mean lung dose of ≥2% and a reduction in the functional lung volume receiving 20 Gy (fV20Gy) of ≥4%, and (2) a mean heart dose ≤30 Gy and relative heart volume receiving 50 Gy of <25%. In total, 19 patients were recruited; 1 withdrew consent. Eighteen patients underwent chemoradiation with FLA. Of the 18 patients, 15 met criteria for feasibility. All patients completed the entire course of chemoradiation therapy. Using FLA resulted in an average reduction of the functional mean lung dose of 12.4% (SD, ±12.8%) and a mean relative reduction of the fV20Gy of 22.9% (SD, ±11.9%). At 12 months, Kaplan-Meier estimates for overall survival were 83% (95% CI, 56%-94%) and estimates for progression-free survival were 50% (95% CI, 26%-70%). Quality-of-life scores were stable across all time points. Using 68Ga-4D-V/Q PET/CT to image and avoid functional lung is feasible.

Sensitivity Analysis in Economic Evaluations of Immuno-Oncology Drugs: A Systematic Literature Review

ObjectivesThis study aimed to review, assess, and report the characteristics and strategies of sensitivity analyses (SAs) that were performed in the context of published economic evaluations of immuno-oncology drugs. MethodsThe systematic literature search was conducted in Scopus and MEDLINE for articles published from 2005 to 2021. Study selection, based on a predefined set of criteria, was performed by 2 reviewers independently. We included economic evaluations of Food and Drug Administration–approved immuno-oncology drugs that were published in English and assessed the accompanying SAs on a set of items, including the range justification of the baseline parameters within the deterministic SA, the provisions for the correlation/overlay between parameters, and the justification of the chosen parameter distribution for the probabilistic SA, among others. ResultsA total of 98 of 295 publications met the inclusion criteria. A total of 90 studies included a one-way and probabilistic SA and 16 of 98 studies had one-way and scenario analysis, alone or together with probabilistic analysis. Most studies provide explicit references as to the choice of parameters and values; nevertheless, there is a lack of a reference of correlation/overlay between parameters in most of the evaluations. In 26 of 98 studies, the most influential parameter for the incremental cost-effectiveness ratio was the under-evaluation drug cost. ConclusionsMost of included articles contained an SA that was implemented according to commonly accepted published guidance. The under-evaluation drug cost, the estimates of progression-free survival, the hazard ratio for overall survival, and the time horizon of the analysis seem to play an important part in the robustness of the outcomes.

The efficacy and safety of anti-PD-1/PD-L1 in treatment of glioma: a single-arm meta-analysis.

This meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors in patients with glioma. PubMed, EMBASE, Web of Science, and the Cochrane library were searched from inception to January 2023 without language restriction. Primary outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). The risk of bias was assessed by subgroup analysis, sensitivity analysis, and publication bias, including funnel plot, Egger's test, and Begg's test. A total of 20 studies involving 2,321 patients were included in this meta-analysis. In the analysis of the included phase III clinical trials, the forest plot showed that PD-1/PD-L1 inhibitors did not improve the OS (HR=1.15, 95% CI: 1.03-1.29, P=0.02, I2 = 14%) and PFS (HR=1.43, 95% CI: 1.03-1.99, P=0.03, I2 = 87%). In the single-arm analysis, the forest plot demonstrated that the 6-month OS was 71% (95% CI: 57%-83%, I2 = 92%), 1-year OS was 43% (95% CI: 33%-54%, I2 = 93%), and the 2-year OS was 27% (95% CI: 13%-44%, I2 = 97%). The pooled estimate of the median OS was 8.85 months (95% CI: 7.33-10.36, I2 = 91%). Furthermore, the result indicated that the 6-month PFS was 28% (95% CI: 18%-40%, I2 = 95%), 1-year PFS was 15% (95% CI: 8%-23%, I2 = 92%), and the 18-month PFS was 10% (95% CI: 3%-20%, I2 = 93%). The pooled estimate of the median PFS was 3.72 months (95% CI: 2.44-5.00, I2 = 99%). For ORR, the pooled estimate of ORR was 10% (95% CI: 2%-20%, I2 = 88%). We further analyzed the incidence of PD-1/PD-L1 inhibitor-related AEs, and the pooled incidence of AEs was 70% (95% CI: 58%-81%, I2 = 94%). The incidence of AEs ≥ grade 3 was 19% (95% CI: 11%-30%, I2 = 94%). The funnel plot for the median PFS and median OS was symmetric with no significant differences in Egger's test and Begg's test. The sensitivity analysis revealed that our results were stable and reliable. The results of this meta-analysis suggest that anti-PD-1/PD-L1 therapy is relatively safe but could not prolong survival in glioma. More randomized controlled trials are needed to confirm our results. https://www.crd.york.ac.uk/prospero/, identifier CRD42023396057.

Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer

BackgroundStandard first-line chemotherapy for endometrial cancer is paclitaxel plus carboplatin. The benefit of adding pembrolizumab to chemotherapy remains unclear.MethodsIn this double-blind, placebo-controlled, randomized, phase 3 trial, we assigned 816 patients with measurable disease (stage III or IVA) or stage IVB or recurrent endometrial cancer in a 1:1 ratio to receive pembrolizumab or placebo along with combination therapy with paclitaxel plus carboplatin. The administration of pembrolizumab or placebo was planned in 6 cycles every 3 weeks, followed by up to 14 maintenance cycles every 6 weeks. The patients were stratified into two cohorts according to whether they had mismatch repair–deficient (dMMR) or mismatch repair–proficient (pMMR) disease. Previous adjuvant chemotherapy was permitted if the treatment-free interval was at least 12 months. The primary outcome was progression-free survival in the two cohorts. Interim analyses were scheduled to be triggered after the occurrence of at least 84 events of death or progression in the dMMR cohort and at least 196 events in the pMMR cohort.ResultsIn the 12-month analysis, Kaplan–Meier estimates of progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group (hazard ratio for progression or death, 0.30; 95% confidence interval [CI], 0.19 to 0.48; P<0.001), a 70% difference in relative risk. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo (hazard ratio, 0.54; 95% CI, 0.41 to 0.71; P<0.001). Adverse events were as expected for pembrolizumab and combination chemotherapy.ConclusionsIn patients with advanced or recurrent endometrial cancer, the addition of pembrolizumab to standard chemotherapy resulted in significantly longer progression-free survival than with chemotherapy alone. (Funded by the National Cancer Institute and others; NRG-GY018 ClinicalTrials.gov number, NCT03914612.)

Outcomes associated with treatment to all sites of disease in patients with stage IVB cancer of the cervix

ObjectiveThe use of chemoradiation in patients with stage IVB cancer of the cervix was evaluated to determine if definitive treatment offers benefit.MethodsA database of 546 patients with cancer of the...