bluuebunny/crossref_metadata_2025 huggingface dataset:
RE-MIND study: A propensity score-based 1:1 matched comparison of tafasitamab + lenalidomide (L-MIND) versus lenalidomide monotherapy (real-world data) in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).
Authors: Nowakowski Grzegorz S. , Rodgers Thomas David , Marino Dario , Frezzato Maurizio , Barbui Anna Maria , Castellino Claudia , Meli Erika , Fowler Nathan Hale , Feinberg Bruce A. , Tillmanns Sascha , Parche Stephan , Fingerle-Rowson Guenter , Winderlich Mark , Ambarkhane Sumeet Vijay , Salles Gilles A. , Zinzani Pier Luigi
Published: May 2020

8020

Background: Patients with R/R DLBCL ineligible for autologous stem cell transplant (ASCT) have a poor prognosis. In these patients, tafasitamab (anti-CD19 antibody) plus lenalidomide (LEN) has shown encouraging results in the open-label, single-arm, phase II L-MIND study (n = 81; NCT02399085). To evaluate the contribution of tafasitamab to the activity of this doublet, we conducted a global, real-world study of patients treated with LEN monotherapy (RE-MIND; NCT04150328). Here we present the primary analysis of a 1:1 patient-level matched comparison between the L-MIND and RE-MIND cohorts. Methods: Patients treated with LEN monotherapy for R/R DLBCL were enrolled in the observational, retrospective RE-MIND cohort. As in L-MIND, patients had 1–3 prior systemic therapies, including ≥1 CD20-targeting regimen; were aged ≥18 years; and were not eligible for ASCT. A 1:1 estimated propensity score (ePS) matching methodology ensured balancing of nine pre-specified baseline covariates. The primary analysis set, Matched Analysis Set 25 (MAS25), included patients who received a LEN starting dose of 25 mg/day. The primary endpoint was investigator-assessed best objective response rate (ORR). Key secondary endpoints included overall survival (OS) and complete response (CR) rate. Results: 490 patients were enrolled in RE-MIND across 58 centers in the US and Europe, of which 140 fulfilled the ePS matching criteria. The MAS25 included 76 patients each from the two cohorts. Baseline characteristics between cohorts were comparable. The primary endpoint was met with a significantly better ORR of 67.1% (95% CI: 55.4–77.5) for the L-MIND cohort versus 34.2% (95% CI: 23.7–46.0) for the RE-MIND cohort (odds ratio 3.89; 95% CI: 1.90–8.14; p < 0.0001). The CR rate was 39.5% (95% CI: 28.4–51.4) in the L-MIND cohort and 13.2% (95% CI: 6.5–22.9) in the RE-MIND cohort. A significant difference in OS favored the L-MIND cohort (HR = 0.499; 95% CI: 0.317–0.785). ORR and CR outcomes in the RE-MIND cohort were similar to the published literature for LEN monotherapy in R/R DLBCL. Conclusions: Significantly better ORR, CR and OS indicate potential synergistic effects of the tafasitamab + LEN combination in ASCT-ineligible R/R DLBCL. ePS-based 1:1 matching allows robust estimation of the treatment effect of tafasitamab when added to LEN. RE-MIND demonstrates the utility of real-world data in interpreting non-randomized trials. Clinical trial information: NCT04150328 .
Impact of premature venetoclax (Ven) discontinuation/interruption on outcomes in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Phase III MURANO study results.
Authors: Mato Anthony R. , Sharman Jeff P. , Biondo Juliana , Wu Mei , Mun Yong , Kim Su Young , Humphrey Kathryn , Boyer Michelle , Zhu Qian , Seymour John F.
Published: May 2020

8028

Background: Ven + rituximab (VenR) has a manageable safety profile and improves survival in patients (pts) with R/R CLL, but discontinuation/interruption is frequent. We present new data from the Phase III MURANO study on the impact of Ven early discontinuation/interruption on outcomes in pts with R/R CLL. Methods: Time-dependent Cox proportional hazards regression models, stratified by 17p deletion and risk status, evaluated the impact of Ven discontinuation/interruption on investigator-assessed PFS and OS. Analyses were performed retrospectively (without type-1 error control) in intent-to-treat pts with R/R CLL from the fixed-duration VenR arm of MURANO (NCT02005471; data cut-off: May 8, 2019). Results: 140/194 pts (72%) in the VenR arm completed 2 years of therapy. Early discontinuation occurred in 54/194 (28%) pts (adverse events [AEs]: 29, disease progression [PD]: 12, withdrawal: 5, physician decision: 3, death: 2, other: 2, non-compliance: 1). Median Ven durations for pts discontinuing due to AEs and PD: 11.3 (0.5–24.6) and 17.1 (4.6–25.1) months, respectively (p = 0.08). Inferior PFS was observed in pts who discontinued Ven early for any reason except PD or due to AEs, versus those who completed therapy (Table). Greater cumulative Ven exposure significantly reduced risk of a PFS/OS event (PFS: HR 0.93, 95% CI 0.88–0.99, p = 0.0168; OS: HR 0.85, 95% CI 0.79–0.92, p < 0.0001). Treatment interruption for AEs occurred in 134/194 (69%) pts, most commonly due to neutropenia (84/194; 43%), per protocol requirements. Median duration of interruption: 9 (1–93) days. Treatment interruption, regardless of duration, had no impact on PFS or OS (Table). 36 (19%) pts with interruptions later discontinued Ven. Conclusions: In MURANO, early Ven discontinuation was associated with suboptimal outcomes; Ven interruption was not. These data highlight the importance of effective control of toxicity to realize the full benefit of VenR treatment. Clinical trial information: NCT02005471 . [Table: see text]
Machine learning prediction of survival in diffuse large B-cell lymphoma based on gene-expression profiling.
Authors: Merdan Selin , Subramanian Kritika , Ayer Turgay , Koff Jean Louise , Chang Andres , Weyenbergh Johan Van , Flowers Christopher
Published: May 2020

8047

Background: The current clinical risk stratification of Diffuse Large B-cell Lymphoma (DLBCL) relies on the International Prognostic Index (IPI) comprising a limited number of clinical variables but is imperfect in the identification of high-risk disease. Our study aimed to: (1) develop a risk prediction model based on the genetic and clinical features; and (2) evaluate the model’s biological implications in association with the estimated profiles of immune infiltration. Methods: Gene-expression profiling was performed on 718 patients with DLBCL for which RNA sequencing data and clinical covariates were available by Reddy et al (2017). Unsupervised and supervised machine learning methods were used to discover and identify the best set of survival-associated gene signatures for prediction. A multivariate model of survival from these signatures was constructed in the training set and validated in an independent test set. The compositions of the tumor-infiltrating immune cells were enumerated using CIBERSORT for deconvolution analysis. Results: A four gene-signature-based score was developed that separated patients into high- and low-risk groups with a significant difference in survival in the training, validation and complete cohorts (p < 0.001), independently of the IPI. The combination of the gene-expression-based score with the IPI improved the discrimination on the validation and complete sets. The area-under-the-curve at 2 and 5 years increased from 0.71 and 0.69 to 0.75 and 0.74 in the validation set, respectively. Conclusions: By analyzing the gene-expression data with a systematic approach, we developed and validated a risk prediction model that outperforms existing risk assessment methods. Our study, which integrated the profiles of immune infiltration with prognostic prediction, unraveled important associations that have the potential to identify patients who could benefit from the various therapeutic interventions, as well as highlighting possible targets for new drugs.
Phase Ib trial combining rapid determination of drug-drug interaction (DDI) followed by a dose finding period to assess safety and preliminary efficacy of fimepinostat plus venetoclax in patients with aggressive B-cell lymphoma.
Authors: Phillips Tycel Jovelle , De Vos Sven , Westin Jason , Barta Stefan K. , Cohen Jonathon Brett , Patel Krish , Smith Sonali M. , Pagel John M. , Kansra Vikram , Grayson Dena , Younes Anas , Batlevi Connie Lee
Published: May 2020

8056

Background: Fimepinostat (F), a dual inhibitor of PI3K (α, β, δ) and HDACs type 1/2, causes suppression of MYC levels (Shulman et al., 2017). A pooled analysis of diffuse large B-cell lymphoma (DLBCL) pts treated with F in two Ph 1/2 trials revealed an objective response rate in evaluable/ITT MYC-altered DLBCL pts of 29%/23%, respectively (Landsburg et al., 2018). Based on compelling preclinical activity of F in combination with venetoclax (V) (a Bcl2 inhibitor), we initiated a Ph 1b/2 study of F + V in pts with relapsed or refractory (R/R) DLBCL or high-grade B-cell lymphoma (HGBL), with or without MYC alteration. V is metabolized primarily by CYP3A, and preclinical studies showed that F may inhibit CYP3A4 (IC50 of 13.58 and 0.28 µM for midazolam and testosterone, respectively), suggesting F could cause DDI with V. Methods: Cohorts of patients received increasing dose levels of F administered on a 5-days-on/2-days-off (5/2) schedule in combination with daily V in 21-day cycles (Cohort 1: F 30 mg QD 5/2 + V 400 mg QD; Cohort 2: F 60 mg QD, 5/2 + V 400 mg QD; Cohort 3: F 60 mg QD 5/2 + V 800 mg QD). A potential DDI was assessed during Cycle 0 (Table), where PK for V (10 mg) monotherapy was compared to that for V (10 mg) in the presence of F. Patient PK samples were collected, analyzed and reviewed in < 10 days to determine the final ramp-up dose level of V. Results: As of 1-Feb-2020, 16 pts have been enrolled in 2 dose cohorts. Intensive PK analysis of 13 pts showed only mild (≤ 2-fold) to no increase in V exposure in the presence of F. In Cohort 1 (n = 6), the mean AUC increased 1.6-fold, and mean Cmax by 1.5-fold. In Cohort 2 (n = 7), no increase in mean AUC (0.9-fold) or Cmax (1.0-fold) was observed. Accordingly, all pts ramped up V to 100% of the target dose (400 mg) upon entering Cycle 1; rapid escalation of V was well tolerated. DLT was observed in 1 pt (Grade 3 diarrhea) in Cohort 2. Overall, 75% of TEAEs have been mild or moderate (Grade 1/2), and most were of limited duration. 11 pts (69%) experienced SAEs; 4 pts (25%) had SAEs considered related to either F or V. Conclusions: Real-time PK evaluation showed that F had only a mild to no DDI with V. F + V is well tolerated at clinically active dose levels, and evaluation of higher dose-level cohorts was ongoing. Enrollment in Cohort 2 remains on-going. Clinical trial information: NCT01742988 . [Table: see text]
Safety and efficacy of TQ-B3525, a novel and selective oral PI3K α/δ inhibitor, in Chinese patients with advanced malignancies: A phase I dose-escalation and expansion trial.
Authors: Wang Huaqing , Jiang Wenqi , Li Su , Wang Yu , Sun Peng , Zhou Pei , Zheng Yang , Zhan Jing , Li Zhiming
Published: May 2020

8058

Background: TQ-B3525 is a novel and selective oral PI3K α/δ inhibitor with activity 41 and 138 folds higher than Buparlisib against PI3K α and PI3K δ in pre-clinical research. This Phase I study (NCT03510767) assessed the safety, tolerability, pharmacokinetics and antitumor activity of TQ-B3525 in Chinese patients with advanced malignancies. Methods: Patients with relapsed or refractory (R/R) lymphoma who have experienced at least two prior systemic anti-cancer treatments, and advanced solid tumor who have failed standard anti-cancer treatment, were enrolled. TQ-B3525 was administered orally from 2mg, 5mg, 10mg, 20mg once daily (qd) to 10mg, 20mg twice daily (bid). DLT was observed in the first cycle (28 days) of dose-escalation phase. Dose-expansion phase started at the dose level which objective response occurs. Results: Between June 2018 and December 2019, a total of 40 patients were enrolled, Including 27 patients with R/R lymphoma and 13 patients with advanced solid tumor. Three DLTs (both grade 3 hyperglycemia) were observed: two in the 20mg bid dose cohort and one in the 10mg bid. The common AEs of all grades were hyperglycemia (65.0%), glycosylated hemoglobin increased (35.0%) and diarrhea (32.5%). Grade 3 or 4 treatment-related AEs occurred in 11 patients (27.5%), with the most common one also being hyperglycemia (10.0%). TQ-B3525 was rapidly absorbed (Tmax: 1-2 h) and moderately eliminated (T1/2: 10-12 h). At steady state, the geometric mean AUC0-24 and Ctrough of TQ-B3525 at 20mg qd were 1060.7 ± 198.6 h*ng/mL and 23.4 ± 9.5 ng/mL, which was above IC50 (4.2 ng/ml). 23 lymphoma patients were evaluable for clinical response per 2014 Lugano Classification. The overall response rate (ORR) was 60.9% (95% CI, 38.5-80.2). The ORR at ≥10mg qd was 70.0% (14/20, [95% CI, 49.9-90.1]). For R/R FL, the ORR was 72.7% (8/11, [95% CI, 46.4-99.1]). At data cut-off (2nd February, 2020), the median PFS for lymphoma was not reached (events rate: 33.3%). The longest duration of response at data cutoff was 11.8 months in a patient with FL. Conclusions: TQ-B3525 is well-tolerated in Chinese patients with advanced malignancies, and demonstrated high promising antitumor activity in R/R lymphoma patients. Recommended phase II dose was established at 20mg qd. A single-arm phase 2 trial of TQ-B3525 in patients with R/R FL is currently underway. Clinical trial information: NCT03510767 .
The BCR repertoire comparison, lymphoma typing model and OS predicted model in 5 different pathological lymphomas: T-LBL/ALL, PTCL-NOS, B-MCL, B-FL, and DLBCL.
Authors: Jiang Wenhua , Zhou Shiyong , Li Jian , Gao Mingyou , Zhao Kuo , Zhang Limeng , Xie Xiaojing , Zhao Ning , Tian Caijuan , Xu Zanmei , Zhang Zhenzhen , Yan Fang , Pan Yi , Liu Pengfei
Published: May 2020

8059

Background: Lymphatic system cancer is characterized by high heterogeneity in histology and clinical manifestations, B-cell antigen receptor (BCR) plays a vital role in anti-tumor immune responses. This study aimed to compare the BCR repertoire and identify some specific immune markers for different pathological lymphomas. Methods: 5 pathological types of non-Hodgkin's lymphoma (T-LBL/ALL, PTCL-NOS, B-MCL, B-FL, DLBCL) were collected, with reactive lymph node (RLN) hyperplasia as control. All patients were tested by high-throughput immunohistochemical sequencing (HTS-IR) to analyze the correlation between B-cell immunohistochemistry and clinical indicators, and constructed new strategy typing and overall survival (OS) predicted models for lymphomas. Results: The BCR repertoire had the highest diversity in RLN, followed by T-LBL/ALL, PTCL-NOS, DLBCL, B-MCL and B-FL. The diversity of BCR repertoire and similarity of B cell antigens were higher in B-MCL and B-FL patients. Similar to RLN, T-LBL/ALL and PTCL-NOS had broad and diverse V-J pairs, and rare in B-MCL, B-FL and DLBCL. RLN patients were with the highest average number of amino acids, followed by T-LBL/ALL, DLBCL, PTCL-NOS, B-MCL and B-FL. The expressed amino acid sequencing of ARDLIALDY, ARRPGSFDY, ARDIAGWGAVAGLLGRAYYGMDV, and ARDGPYGGNSVEYFQH were markedly different among 5 groups. Patients tended to recurrence expressed ASLDSSPSGFC, ARGMTTVTTAPNY, ARVPLYDDQNINDV and AGGVGGYDWGSYYFDY (P = 0.01605, 0.02869, and 0.01569), and prone to metastasis with expressions of ARVKEFYGILTGYDY, AHSIIGSSWYNWFDP and VRDGGWQSNNWLGFDV (P = 0.04259, 0.0450 and 0.0481). For all patients, 18 (7 negative, 11 positive) and 12 (10 negative, 2 positive) IGH V-J pairs were respectively associated with lymphoma recurrence and metastasis. The top 3 most significant pairs were IGHV7-4-1_IGHJ4, IGHV3-53_IGHJ5 and IGHV3-7_IGHJ5 bound up with recurrence (P = 0.0019, 0.0020 and 0.0021), and IGHV3-74_IGHJ1, IGHV1-69_IGHJ3 and IGHV1-2_IGHJ1 related to metastasis (P = 0.0022, 0.010 and 0.019). The accuracy of typing model in training and test sets was 78.125% (25/32) and 60% (6/10), respectively. The OS model can predict long (≥ 24 months) or short ( < 24 months) OS. Conclusions: Our study identified new biomarkers, constructed novel lymphoma typing model and OS predicted model based on B cell repertoire. It provides a comprehensive understanding of immune response, and contributes to the diagnosis and prognosis of non-Hodgkin's lymphoma.
Update of CARTITUDE-1: A phase Ib/II study of JNJ-4528, a B-cell maturation antigen (BCMA)-directed CAR-T-cell therapy, in relapsed/refractory multiple myeloma.
Authors: Berdeja Jesus G. , Madduri Deepu , Usmani Saad Zafar , Singh Indrajeet , Zudaire Enrique , Yeh Tzu-Min , Allred Alicia J. , Olyslager Yunsi , Banerjee Arnob , Goldberg Jenna D. , Schecter Jordan , Geng Dong , Wu Xiaoling , Carrasco-Alfonso Marlene , Rizvi Syed , Fan Frank (Xiaohu) , Jakubowiak Andrzej J. , Jagannath Sundar
Published: May 2020

8505

Background: JNJ-68284528 (JNJ-4528) is a chimeric antigen receptor T (CAR-T) cell therapy containing 2 BCMA-targeting single-domain antibodies. Here we present updated CARTITUDE-1 (NCT03548207) phase 1b results with longer follow-up. Methods: Pts had MM per IMWG criteria, measurable disease, received ≥3 prior regimens or were double refractory to a PI and IMiD, and received anti-CD38 antibody. Cyclophosphamide 300 mg/m2+ fludarabine 30 mg/m2 over 3 days were used for lymphodepletion. JNJ-4528 (median, 0.73x106 CAR+ viable T cells/kg) was given as a single infusion. Cytokine release syndrome (CRS) was graded by Lee et al2014 and neurotoxicity by CTCAE, v5.0 and ASTCT grading. Response was assessed per IMWG criteria. Results: As of 17 Jan 2020, median follow-up is 9 mo (3–17). Phase 1b enrollment is complete (N = 29 treated; median 5 (3–18) prior lines, 76% penta-exposed, 86% triple-refractory, 31% penta-refractory, 97% refractory to last line of therapy). Most frequent adverse events (AEs) were neutropenia (100%), CRS (93%), and thrombocytopenia (93%). Grade (Gr) ≥3 hematologic AEs were neutropenia (100%), thrombocytopenia (69%), and leukopenia (59%). 27 (93%) pts had CRS; 25 Gr 1–2, 1 Gr 3, and 1 Gr 5 (day 99 subsequent to dose-limiting toxicity of prolonged Gr 4 CRS). Median time to onset of CRS was 7 days (2–12). 4 pts had treatment-related neurotoxicity: 3 Gr 1–2 and 1 Gr 3. ORR was 100%, with 22 (76%) stringent complete responses (sCRs), 6 (21%) very good partial responses (VGPRs), and 1 (3%) PR. Median time to ≥CR was 2 mo (1–9). 26/29 pts are progression-free, with 6-mo progression-free survival rate of 93% and longest response ongoing at 15 mo. 1 death due to CRS and 1 to acute myeloid leukemia (not treatment-related) occurred during the study. All 16 pts (14 sCR, 2 VGPR) evaluable at 6 mo were minimal residual disease negative at 10−5 or 10−6. JNJ-4528 CAR+ T cell expansion peaked between day 10–14. At 6-mo individual follow-up, 22/28 pts had JNJ-4528 CAR+ T cells below the level of quantification (2 cells/µL) in peripheral blood, suggesting CAR-T persistence in peripheral blood did not seem to correlate with deepening of response. At peak expansion, preferential expansion of CD8+ CAR-T cells with a central memory phenotype was observed in peripheral blood. Conclusions: JNJ-4528 treatment led to responses in all pts. These responses were early, deep, and durable at a low dose of CAR-T cells with 26/29 (90%) pts progression free at median 9-mo follow-up. CRS was manageable in most pts, supporting outpatient dosing. Clinical trial information: NCT03548207 .
Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM).
Authors: Hari Parameswaran , Pasquini Marcelo C. , Stadtmauer Edward Allen , Fraser Raphael , Fei Mingwei , Devine Steven Michael , Efebera Yvonne Adeduni , Geller Nancy , Horowitz Mary M. , Koreth John , Landau Heather Jolie , McCarthy Philip L. , Qazilbash Muzaffar H. , Shah Nina , Vesole David H. , Vogl Dan T. , Somlo George , Krishnan Amrita Y. , Giralt Sergio
Published: May 2020

8506

Background: STaMINA was a phase III trial comparing progression-free survival (PFS) among 758 pts randomized to: 1. second autoHCT then lenalidomide (Len) maintenance (Auto/Auto, n = 247); 2. consolidation with Len/bortezomib/ dexamethasone (RVD) followed by Len maintenance (Auto/RVD, 254); 3. Len maintenance (Auto/Len, 257). All three arms were similar (Stadtmauer JCO 2018). Len maintenance was designed to continue for 3 years and amended to allow continuation until disease progression through a follow up protocol (07LT, NCT#02322320). We report 6 yr follow up for STaMINA and the results of Len discontinuation beyond 3 years. Methods: 07LT was offered to pts who were progression-free at 38 mo; completed planned Len maintenance and were within 4 years of BMT CTN 0702 follow up. Among 431 07LT eligible patients, 273 enrolled and 179 opted to continue maintenance until disease progression. All patients enrolled in STaMINA were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) and long-term outcomes for patients not enrolled on 07LT (N = 166) were available through this mechanism. Before combining 07LT data and CIBMTR data for LTFU analysis, outcomes in both databases were analyzed separately and confirmed to be comparable. Results: Using intent-to-treat (ITT), 6yr PFS and overall survival (OS) was the same among Auto/Auto (43.9%; 73.1%), Auto/RVD (39.7%, 74.9%) and Auto/Len (40.9%, 76.4%)(p = 0.6; p = 0.8). Protocol defined high risk disease, (HR = 1.53, p < 0.0001) and age (p = 0.03) were adverse risks for PFS. In as treated analysis, 6yr PFS were 49.4%, 39.7% and 38.6% for Auto/auto (170), Auto/RVD (222) and Auto/Len (361), respectively (p = 0.01). 6yr PFS in high risk pts as treated analysis were 43.6% and 26% for Auto/auto and Auto/Len, respectively (p = 0.03). Landmark analysis at 38 mo included 215 pts who continued Len maintenance (either on 07LT study or commercial Len) vs. 207 who stopped. Baseline demographics; study arm on 0702, induction pre-autoHCT were similar. Len discontinuation after 38 mo was associated with inferior PFS (79.5% vs. 61% at 5yr; HR = 1.91, p = 0.0004) but similar OS. Incidence of all second primary malignancies (SPM)(81 cases with 43 heme-malignancies) was associated with age. Conclusions: Long term outcomes are similar using ITT, but as treated analysis suggested a PFS benefit for tandem autoHCT, driven mainly by pts with high risk MM. Len discontinuation even at 38 mo was associated with inferior PFS. Clinical trial information: NCT02322320 .
Primary analysis of the randomized phase II trial of bortezomib, lenalidomide, dexamthasone with/without elotuzumab for newly diagnosed, high-risk multiple myeloma (SWOG-1211).
Authors: Usmani Saad Zafar , Ailawadhi Sikander , Sexton Rachael , Hoering Antje , Lipe Brea , Hita Sandi , Durie Brian G. , Zonder Jeffrey A. , Dhodapkar Madhav V. , Callander Natalie Scott , Rajkumar S. Vincent , Voorhees Peter Michael , Richardson Paul G. , Orlowski Robert Z.
Published: May 2020

8507

Background: The introduction of immunomodulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT) has improved outcomes for patients with multiple myeloma (MM), but those with high risk MM (HRMM) have a poor long-term prognosis. To date, no trials have addressed optimal treatment for these patients. Methods: S1211 is a randomized phase II trial (NCT01668719) comparing 8 cycles of lenalidomide, bortezomib and dexamethasone (RVd) induction followed by dose-attenuated RVd maintenance until disease progression with or without elotuzumab. Stem cell collection was allowed, but ASCT was deferred until progression. HRMM was defined by one of the following: gene expression profiling high-risk (GEPhi), t(14; 16), t(14; 20), del(17p) or amplification 1q21, primary plasma cell leukemia (pPCL) and elevated serum LDH (> 2X ULN). Median progression-free survival (PFS) was the primary end-point, using a one-sided stratified log-rank test at a one-sided significance level of 0.1. Secondary endpoints included overall response rate (ORR), adverse events (AE), serious adverse events (SAE) and OS. Response was assessed using the IMWG 2009 criteria. Results: S1211 enrolled 103 evaluable patients, RVd n = 54, RVd-Elo n = 49. 75% had ISS II/III, 47% amp1q21, 38% del17p, 12% t(14; 16), 9% GEPhi, 7% pPCL, 5% t(14; 20) and 4% elevated serum LDH (18.5% > 1 feature). With median follow-up of 53 months (mos.), no difference in median PFS was observed [RVd-Elo = 31 mos., RVd = 34 mos.,HR = 0.968 (80% CI = 0.697-1.344), p = 0.449]. No difference in OS was observed [RVd-Elo = 68 mos, RVd = not reached, HR = 1.279 (80% CI: 0.819, 2.000), p-value = 0.478]. 72% pts had > Grade 3 AEs, no differences in the safety profile were observed except >Grade 3 infections (RVd 8%, RVd-Elo 16%), >Grade 3 sensory neuropathy (RVd 8%, RVd-Elo 13%). Conclusions: In the first randomized HRMM study reported to date, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. However, the PFS and OS seen in both arms of the study exceeded the original statistical assumptions and support the role for PI/IMiD combination maintenance therapy for this patient population. The S1211 data will serve as an important benchmark for future HRMM clinical trials. Clinical trial information: NCT01668719 .
Selinexor, daratumumab, and dexamethasone in patients with relapsed/refractory multiple myeloma (MM).
Authors: Gasparetto Cristina , Lentzsch Suzanne , Schiller Gary J. , Callander Natalie Scott , Tuchman Sascha , Bahlis Nizar J. , White Darrell , Chen Christine , Baljevic Muhamed , Sutherland Heather J , Kotb Rami , Sebag Michael , LeBlanc Richard , Venner Christopher P , Bensinger William , Rossi Adriana C. , Sheehan Heidi , Arazy Melina , Kai Kazuharu , Lipe Brea
Published: May 2020

8510

Background: Selinexor is a first-in-class oral Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates exportin 1 (XPO1). Selinexor in combination with low dose dexamethasone (Sel-dex) was approved by the FDA, based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients (pts) with relapsed/refractory MM (RRMM). Single agent daratumumab has demonstrated an ORR of 29% in MM reftactory to proteasome inhibitors (PIs)/immunomodulatory drug (IMiDs). We evaluated the safety, tolerability and preliminary efficacy of the combination of Sel-dex and daratumumab (SDd) in pts with MM refractory to PIs/IMiDs. Methods: This is a multicenter, open-label, phase 1b/2 dose escalation and expansion study. Pts were eligible if they had received ≥ 3 prior lines of therapy, including a PI and an IMiD, or whose MM was refractory to a PI and an IMiD. In the expansion phase, pts were required to be anti-CD38 monoclonal antibody-naïve. One dose level was tested at each schedule: selinexor once-weekly (QW at 100 mg) or twice-weekly (BIW at 60 mg) with dexamethasone 40 mg. Daratumumab 16 mg/kg IV was administered per label. Primary objective was to determine the maximum tolerated dose and recommended phase 2 dose (RP2D), and assess safety, tolerability and efficacy of SDd in pts with RRMM. Results: A total of 34 pts were enrolled; 3 in the 60 mg BIW and 31 in the 100 mg QW cohorts. Median age was 69 and median number of prior treatment regimens was 3 (range, 1–10). Out of 34 pts, 62% and 65% were refractory to bortezomib and lenalidomide respectively. Common treatment related adverse events (all grades, grades 3/4) included: thrombocytopenia (71%, 47%), fatigue (62%, 18%), nausea (71%, 9%), anemia (62%, 32%) and neutropenia (50%, 26%). Two dose limiting toxicities (DLTs) were reported in the 60 mg BIW cohort: Grade 3 thrombocytopenia and Grade 2 fatigue requiring dose reduction in selinexor to 100 mg QW. In the 100 mg QW escalation cohort (n = 6), no DLTs occured. 32 patients were evaluable for efficacy. The ORR was 73% (11 VGPR, 11 PR) for 30 daratumumab-naïve pts. Median progression-free survival was 12.5 months in both groups. Conclusions: Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, daratumumab 16 mg/kg and dexamethasone 40 mg, administered QW. In pts with PI and IMiD refractory MM, weekly SDd demonstrated promising activity with an ORR of 73% in daratumumab-naïve pts and a median PFS of 12.5 months. This supports further development of a novel non-PI, non-IMiD backbone in earlier lines of therapy. Clinical trial information: NCT02343042 .
Will adding alkylating agent to bortezomib improve survival of newly diagnosed AL amyloidosis patients?
Authors: Zhang Yumeng , Duncanson Lauren , Nishihori Taiga , Hansen Doris K. , Ochoa-Bayona Jose L. , Liu Hien D , Baz Rachid C. , Blue Brandon Jamaal
Published: May 2020

8517

Background: The combination of bortezomib (Bort) and alkylating agent (AA) is a frequently used first-line therapy for AL amyloidosis. Kastritis et al. compared melphalan and dexamethasone with or without bortezomib as primary therapy and demonstrated increased hematologic response rate with the bortezomib and melphalan combination. However, the role of AA is unclear. This study aimed to evaluate if adding AA to Bort improved patient outcomes in AL amyloidosis. Methods: We retrospectively reviewed clinical data on 209 patients with systemic AL Amyloidosis at Moffitt Cancer Center between 2008 and 2020. We excluded patients with localized amyloidosis or amyloid other than AL. Patients were divided into two groups based on upfront therapy: A) Bort and B) Bort + AA. All patients also received dexamethasone. The staging was per Mayo 2012. Organ involvement, response, and progression were defined based on the 2005 criteria. Overall survival (OS) was defined as the time from initial diagnosis until death or last contact. Time to next therapy (TTNT) was calculated in patients with the documented hematologic response from the time of initiation of therapy to time of the next therapy/last follow up/death. Results: Of 209 patients, 36% (n=76) received Bort+AA; 30% (n=62) received Bort. No significant difference in clinical characteristics was seen in both groups except for age (which was higher for arm A: median 65 and 62 years, respectively, p=0.043) (table). In addition, Bort+AA became more commonly used as a frontline therapy after 1/1/2014 (p=0.001). Group A and B had similar median OS (69.9 months [95% CI. 44.7-95.2] and 64.4 mo [95% CI 40.5-88.3] respectively, p=0.60). 86% of patients in group B achieved a hematologic response as compared to 74% of patients in group A (p=0.15). Similarly, 47% of patients in group B achieved an organ response as compared to 34% of patients in group A (p=0.22). TTNT was higher in group A than group B (16.9 mo [95% CI, 0-41.5] and 7.8 mo [95% CI, 3.5-12.0], respectively, p=0.08). Conclusions: While Bort+AA is a commonly used regimen for amyloidosis, the addition of AA to Bort did not result in superior OS, TTNT compared to Bort alone in this retrospective study. This finding should be confirmed in prospective studies. Baseline Characteristics. [Table: see text]
Prospective evaluation of spatial heterogeneity at single cell resolution in multiple myeloma.
Authors: Merz Maximilian , Merz Almuth Maria Anni , Wang Jie , Wei Lei , Hu Qiang , Belal Ahmed , Alberico Ronald , Block Anne Marie W. , Herr Megan , Hahn Theresa , Wallace Paul K , Tario Joseph , Luce Jesse , Glenn Sean , Singh Prashant , Liu Song , McCarthy Philip L. , Hillengass Jens
Published: May 2020

8524

Background: Osteolytic lesions (OL) characterize symptomatic multiple myeloma (MM). It is still unclear why plasma cells (PC) cause OL in certain regions of the body while other areas show no signs of bone destruction despite significant bone marrow infiltration. We conducted the first study of single cell RNA sequencing (scRNA-seq) and whole-exome sequencing (WES) of PC obtained from random bone marrow samples (RS) and paired OL. Methods: As part of a prospective clinical trial, patients consented to an imaging-guided biopsy of new OL identified by PET/CT in addition to the RS from the iliac crest. Both samples were acquired in the same session. On the same day PC were isolated using a CD138 positive selection kit and single cell gene expression libraries were generated for scRNA-seq. Frozen PC were subjected to DNA extraction and WES. Results: We sequenced 93569 purified, viable PC from paired samples from 15 different locations in the first 7 consecutive patients (median PC from location: 7203; range 1121-10279). Quality assessment of scRNA-seq data revealed no differences between PC in OL and RS. Based on scRNA-seq, 9-24 different subpopulations of PC in individual patients were identified. Over 90% of clusters found in the RS were also present in corresponding OL suggesting a common ancestor. This was true for patients with overlapping as well as divergent mutational profiles in RS and OL as shown by WES. In each patient we found PC clusters that were predominantly present in OL. Respective clusters were characterized by expression of Wnt-signaling inhibitors like DKK-1, Frzb and sFRP-2 and other genes linked to MM bone disease (HGF, CXCL-12, CCL3). Lysosome-associated membrane protein-like molecule 5 (LAMP5) and J-chain were overexpressed in OL clusters. Analysis of genes (IKZF1 and IKZF3) associated with response to treatment and outcome revealed vast heterogeneity and differences in risk scores (UAMS70 and IFM15) on a single cell level from different locations in individual patients. Conclusions: Our study provides the first evidence that PC from OL have distinct transcriptomic profiles that link site-specific gene expression to development of bone disease and adverse outcome.
Multiparameter flow cytometry (MFC) and next generation sequencing (NGS) for minimal residual disease (MRD) evaluation: Results of the FORTE trial in newly diagnosed multiple myeloma (MM).
Authors: Oliva Stefania , Genuardi Elisa , Belotti Angelo , Frascione Pio Manlio Mirko , Galli Monica , Capra Andrea , Offidani Massimo , Vozella Federico , Zambello Renato , Auclair Daniel , Kirsch Ilan , Ruggeri Marina , Jacob Allison , Ledda Antonio , Corradini Paolo , Gilestro Milena , Zamagni Elena , Musto Pellegrino , Boccadoro Mario , Gay Francesca
Published: May 2020

8533

Background: The role of MRD by MFC and NGS is well known in MM, with few data on the concordance of the two techniques. We analyzed and compared MRD data from the FORTE trial both by MFC and NGS. Methods: Newly diagnosed MM patients (pts) ≤65 years were randomized to: carfilzomib, lenalidomide, dexamethasone (KRd) induction-autologous stem cell transplant (ASCT) - KRd consolidation (KRd_ASCT); 12 KRd cycles (KRd12); carfilzomib, cyclophosphamide, dexamethasone (KCd) induction-ASCT-KCd consolidation (KCd_ASCT). Pts were then randomized to maintenance: lenalidomide alone or plus carfilzomib. MRD was assessed by 8-color second generation flow cytometry (sensitivity 10−5) in pts with ≥very good partial response (VGPR) before maintenance. In a subgroup of these pts, next generation flow (NGF; sensitivity 10−5-10−6) was performed. In ≥CR pts, MRD pre-maintenance was also assessed by NGS (Adaptive Biotechnologies; sensitivity 10−5-10−6). Thus, both MFC and NGS evaluations were available only in ≥CR pts. 1-year sustained MRD negativity by MFC and NGS was also analyzed in pts with at least one sample available at least 1 year apart. Results: MFC and NGS data were available in 184/233 (79%) CR pts (66 KRd_ASCT, 67 KRd12 and 51 KCd_ASCT). Median age of this ≥CR population was 57 years (IQR 52-62), 13% had International Staging System (ISS) III and 27% high risk cytogenetics by FISH [either del(17p) or t(4;14) or t(14;16)]. Table reports MRD negativity rate by MFC and NGS at a cut-off of 10−5 and 10−6 among ≥CR negative pts in the 3 arms. NGS negativity at a cut-off 10−6 was found in 36/133 (27%) ≥CR pts (for 51/184 CR pts 10−6 sensitivity was not reached). In evaluable pts, 1-year sustained 10−5 MRD negativity by MFC and NGS was superimposable (83%). We evaluated concordance of MRD results by the two techniques and observed agreement was 86% for MFC and NGS at 10−5 evaluable samples (n: 335; r: 0.61) and 78% for MFC and NGS at 10−6 evaluable samples (n: 56; r: 0.77). Conclusions: In pts who achieved ≥CR, similar rate of pre-maintenance 10−5 negativity by MFC and NGS has been reached in each arm, with 83% pts maintaining 1-year MFC or NGS 10−5 sustained MRD negativity. Concordance between MFC and NGS was good, particularly when the same sensitivity was reached. Longer follow up is needed to draw definitive conclusions. Clinical trial information: NCT02203643 . [Table: see text]
Corticosteriod tapering in patients (Pts) with relapsed or refractory multiple myeloma (RRMM) receiving subcutaneous daratumumab (DARA SC): Part 3 of the open-label, multicenter, phase Ib PAVO Study.
Authors: Nahi Hareth , Usmani Saad Zafar , Mateos Maria-Victoria , van de Donk Niels W.C.J. , Moreau Philippe , Oriol Albert , Plesner Torben , Yang Shiyi , Hellemans Peter , Tromp Brenda J. , Luo Man (Melody) , Zemlickis Donna , Farnsworth Andrew , Chari Ajai
Published: May 2020

8537

Background: Intravenous DARA (DARA IV) is approved for the treatment of MM. In Part 2 of PAVO, DARA SC, a concentrated, pre-mixed SC co-formulation of DARA and recombinant human hyaluronidase PH20 (rHuPH20), was well tolerated, with a low infusion-related reaction (IRR) rate, and showed consistent serum concentrations and similar efficacy to DARA IV in RRMM pts. In PAVO Part 3, we evaluated the safety of pre- and post-dose corticosteroid tapering during DARA SC administration. Methods: RRMM pts with ≥2 prior lines of treatment, including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), received DARA SC (DARA 1,800 mg + rHuPH20 30,000 U in 15 mL) by manual SC injection per approved IV monotherapy dosing schedule. Pts received a 3-week (wk) tapering schedule (corticosteroid-free by Cycle [C] 1 Day [D] 22), with methylprednisolone (MP) given PO/IV pre-dose (C1D1, 100 mg; C1D8, 60 mg; C1D15, 30 mg) and PO post-dose (C1D1, 20 mg for 2 days; C1D8, 20 mg for 1 day; C1D15, 20 mg for 1 day), or a 2-wk tapering schedule (corticosteroid-free by C1D15), with MP given PO/IV pre-dose (C1D1, 100 mg; C1D8, 60 mg) and PO post-dose (C1D1, 20 mg for 2 days; C1D8, 20 mg for 1 day). Results: Pts (3-wk group, n = 15; 2-wk group, n = 15) received a median of 2 (range: 2-7) prior lines of therapy, with 37% refractory to a PI and an IMiD. The 3-wk and 2-wk groups received a median (range) of 14 (2-19+) and 8 (2-16+) DARA SC doses without corticosteroids, respectively. No IRRs were reported in the 3-wk group. 3 pts (20%) in the 2-wk group experienced IRRs on C1D1 (grade 3 hypertension, grade 2 chills, grade 1 pyrexia, grade 1 oropharyngeal pain, and grade 1 tachycardia). IRRs occurred within 2 h of the first DARA SC administration; no IRRs were reported at later administrations. Most common (≥25%) treatment emergent adverse events (TEAEs) were upper respiratory tract infection (40%) and fatigue and nausea (27% each). Most common (≥5%) grade 3/4 TEAEs were anaemia, lymphopenia, neutropenia, and hypertension (7% each). At median follow-up of 6.8 mo (3-wk group) and 2.4 mo (2-wk group), the overall response rates were 40% (95% CI, 16-68%) and 27% (95% CI, 8-55%) and ≥very good partial response rates were 13% (95% CI, 2-40%) and 7% (95% CI, 0-32%), respectively. Conclusions: Rapid corticosteroid tapering over 2 wks is safe in RRMM pts receiving DARA SC. These data help guide future DARA SC combinations (ie, T-cell redirectors, CAR-T, or checkpoint inhibitors), where limiting concurrent corticosteroids may be preferred. Clinical trial information: NCT02519452 .
Ixazomib-dexamethasone (Ixa-Dex) vs physician’s choice (PC) in relapsed/refractory (RR) primary systemic AL amyloidosis (AL) patients (pts) by prior proteasome inhibitor (PI) exposure in the phase III TOURMALINE-AL1 trial.
Authors: Kastritis Efstathios , Dispenzieri Angela , Wechalekar Ashutosh D. , Schönland Stefan O. , Kim Kihyun , Sanchorawala Vaishali , Landau Heather Jolie , Kwok Fiona , Suzuki Kenshi , Comenzo Ray , Palladini Giovanni , Berg Deborah , Liu Guohui , Kumar Arun , Faller Douglas V. , Merlini Giampaolo
Published: May 2020

8546

Background: The PI bortezomib is commonly used in first-line therapy of AL, but new therapies are needed that are tolerable in the context of multi-organ dysfunction and that, in RRAL, offer improved outcomes following prior bortezomib. Ixazomib is an oral PI, and in TOURMALINE-AL1, the first phase 3 trial conducted in RRAL, while the first primary endpoint of hematologic overall response rate (ORR) was not met, all clinically relevant time-to-event endpoint data favored Ixa-Dex vs PC (Dispenzieri et al, ASH 2019). Methods: RRAL pts with 1–2 prior therapies were randomized (1:1) to Ixa-Dex (n = 85) or PC (n = 83; Dex plus lenalidomide [n = 47], melphalan [n = 24], cyclophosphamide [n = 10], or thalidomide [n = 2]), stratified by cardiac stage, relapsed vs refractory disease, and prior PI exposure. The primary endpoints were hematologic ORR and 2-yr rate of vital organ deterioration or death. We report subgroup analyses of ORR and outcomes by prior PI exposure. Results: Of the 168 pts enrolled, 90 were PI-naïve and 78 PI-exposed (46 and 39 in the Ixa-Dex arm; 44 and 39 in the PC arm) per stratification; 28 and 27 pts in the Ixa-Dex and PC arms had received bortezomib in their last prior line. Hematologic ORR was 63% vs 50% for Ixa-Dex vs PC (odds ratio [OR] 1.71; 95% confidence interval [CI] 0.74–3.96) in PI-naïve pts, and 41% vs 51% (OR 0.66; 95% CI 0.27–1.62) in PI-exposed pts. For time-to-event outcomes (Table), hazard ratios (HRs) were 0.46–0.85 in favor of Ixa-Dex vs PC in both PI-naïve and PI-exposed pts. Conclusions: Hematologic ORR was higher with Ixa-Dex vs PC in PI-naïve pts but lower in PI-exposed pts (although not statistically significant), and long-term clinically relevant outcomes favored Ixa-Dex in both groups. Based on HRs, the magnitude of benefit appeared similar or greater in PI-naïve vs PI-exposed pts. Clinical trial information: NCT01659658 . [Table: see text]
Randomized phase II trial comparing the efficacy of standard-dose with high-dose twice-daily thoracic radiotherapy (TRT) in limited disease small-cell lung cancer (LD SCLC).
Authors: Gronberg Bjorn Henning , Killingberg Kristin Toftaker , Fløtten Øystein , Bjaanæs Maria Moksnes , Madebo Tesfaye , Langer Seppo , Schytte Tine , Brustugun Odd Terje , Nyman Jan , Stokke Kristin , Halvorsen Tarje Onsøien
Published: May 2020

9007

Background: Concurrent chemoradiotherapy is the standard treatment of LD SCLC. Some patients are cured, but most relapse and better treatment is needed. 45 Gy in 30 fractions BID is the most recommended TRT-schedule. Studies suggest that a higher TRT-dose might prolong survival, but hitherto, this has not been confirmed in randomized trials. We aimed to investigate whether high-dose BID TRT of 60 Gy in 40 fractions was feasible, tolerated, and improved survival. Methods: Patients > 18 years, performance status (PS) 0-2 and confirmed LD SCLC were to receive 4 courses of platinum/etoposide and were randomized to BID TRT of 60 or 45 Gy. Responders were offered prophylactic cranial irradiation of 25-30 Gy. Primary endpoint was 2-year survival; secondary endpoints were toxicity, progression free survival (PFS), and overall survival (OS). To demonstrate a 25% improvement of 2-year survival from 53% to 66% with a one-sided α = .10 and β = .80, 75 patients were required on each arm. Results: Between 2014-2018, 176 patients were enrolled at 22 Scandinavian hospitals. 160 completed TRT per protocol and were eligible for the present analyses (60 Gy: n = 84, 45 Gy: n = 76). Median age was 65, 58% women, 90% PS 0-1. There were no significant differences in grade 3–4 esophagitis (60 Gy: 19%, 45 Gy: 18%, p = .92) or grade 3–4 pneumonitis (60 Gy: 4%, 45 Gy: 0%, p = .10). There was a trend towards more neutropenic infections on the 45 Gy arm (60 Gy: 21%, 45 Gy: 36%, p = .05). There were no significant differences in other grade 3-4 toxicity. Three patients died during the study treatment period (60 Gy: one neutropenic infection and one aortic dissection; 45 Gy: one thrombocytopenic bleeding). There were no statistically significant differences in response rates (60 Gy: 88% [95% CI 81-95], 45 Gy: 85% [95% CI 76-93], p = .52) or median PFS (60 Gy: 20 months [95% CI 11-29], 45 Gy: 14 months [95% CI 10-19], p = .31). Significantly more patients on the 60 Gy arm were alive after 2 years (60 Gy: 73% [95% CI 63-83], 45 Gy: 46% [95% CI 36-60], p = .001), and they had a significantly longer median overall survival (60 Gy: 42 months [95% CI 32-51], 45 Gy: 23 months [95% CI 17-28], HR .63 [95% CI .41-.96], p = .031). Conclusions: LD SCLC patients who received BID TRT of 60 Gy had a statistically significant and numerically substantial benefit in terms of 2-year survival (primary endpoint) and median overall survival compared with those who received BID TRT of 45 Gy. The higher TRT dose did not cause more toxicity than the standard dose. Clinical trial information: NCT02041845.
The anti-disialoganglioside (GD2) antibody dinutuximab (D) for second-line treatment (2LT) of patients (pts) with relapsed/refractory small cell lung cancer (RR SCLC): Results from part II of the open-label, randomized, phase II/III distinct study.
Authors: Edelman Martin , Dvorkin Mikhail , Laktionov Konstantin K. , Navarro Alejandro , Juan-Vidal Oscar , Kozlov Vadim , Golden Gil , Jordan Odette , Deng CQ
Published: May 2020

9017

Background: Although SCLC is highly responsive to initial therapy, most pts relapse < 1 y. Topotecan (T) and irinotecan (I) are used in 2LT of SCLC; however, treatment response is low: ≤10-25% and median survival is ~4-5 months. Preclinical studies support GD2 as an SCLC target. This study evaluated the combination of D+I vs. I alone or T alone in 2LT of SCLC pts. Methods: Pts with RR SCLC, Eastern Cooperative Oncology Group 0-1, were randomized 2:2:1 to receive D 16-17.5 mg/m2 intravenously (IV) plus I 350 mg/m2 IV (Day 1 q21d), I 350 mg/m2 IV (Day 1 q21d), or T 1.5 mg/m2 IV (Days 1-5 q21d). Randomization was stratified by duration of response to prior platinum therapy. Primary endpoint was overall survival (OS) in pts treated with D+I vs. I alone and was analyzed using stratified log-rank test and COX regression. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate, ORR + stable disease (CBR). Safety was assessed. Results: 471 pts were randomized to D+I (n = 187), I (n = 190), or T (n = 94). Baseline characteristics were balanced (24.2% women; mean ± SD age 61.6 ± 8.7 y). Median OS was similar in pts receiving D+I (6.9 [3.5,10.9] months) vs. I alone (7 [3.6,13.1] months) (HR [95% CI]: 1.12 [0.9,1.4]; P = 0.3132) or T alone (7.4 [3.8,12.8] months) (HR [95% CI]: 1.05 [0.8,1.37]; P = 0.7233). Median PFS was similar in pts receiving D+I (3.5 [1.5,6.2] months) vs. I (3 [1.4,5.7] months) or T (3.4 [1.6, 6.1] months) alone. ORR was similar in pts receiving D+I (17.1%) vs. I (18.9%) or T (20.1%) alone. CBR was similar in pts receiving D+I (67.4%) vs. I (58.9%) or T (68.1%) alone. Grade 3 or higher adverse events were experienced by 77% D+I, 69.5% I, and 86.4% T pts. Conclusions: Treatment with D+I was not superior to established 2LT for RR SCLC. Exploratory analyses are ongoing to evaluate GD2 expression in circulating tumor cells, select protein biomarkers, and any correlative impact on observed response. Clinical trial information: NCT03098030.