Response Rate In Pts Research Articles

Genomic alterations in circulating tumor DNA (ctDNA) and response to telisotuzumab adizutecan (ABBV-400) treatment in patients (pts) with colorectal cancer (CRC).

258 Background: Telisotuzumab adizutecan is an antibody-drug conjugate comprising the c-Met–targeting antibody telisotuzumab conjugated to a topoisomerase 1 inhibitor payload, adizutecan. A phase 1 trial (NCT05029882) in advanced solid tumors reported higher response rates in pts with CRC and high c-Met expression. We present an analysis of responses based on genomic alterations in ctDNA. Methods: Pts with CRC that is refractory to standard treatment were enrolled. Telisotuzumab adizutecan was given IV Q3W. ctDNA was isolated from baseline (BL) and cycle 3, day 1 plasma samples and analyzed with the GuardantINFINITY assay. Circulating tumor fraction (cTF) was estimated on the basis of variant allele frequency of somatic mutations in a 74-gene panel and methylation signals across targeted regions of the GuardantINFINITY methylation panel. Molecular response (MR) was defined as 50% decrease in cTF from BL. Radiographic response (RR) was assessed by RECIST v1.1. Results: Overall, 113 pts had both BL ctDNA and RR data. Confirmed ORR was 18% (20/113). The most prevalent gene alterations included TP53 (75%), APC (68%), and KRAS (66%) mut; PTPRT (56%), ASXL1 (53%), and FLT1 (52%) amp; SMAD4 (44%) and TP53 (43%) deletions; and MET (4%), BRAF , FGFR3, and NRG1 (all 3%) fusions. The Table shows RRs in pts with specific CRC biomarkers, and MR using the 2 panels with corresponding clinical outcomes. RRs were seen in pts with positive plasma samples at BL for TMB, RAS, BRAF, and HER2. MRs were detected in 64% and 65% of pts using the 74-gene and methylation panel, respectively. ORR was higher in pts with MR (35%) than without MR (8%) using the 74-gene, and 35% vs 0% using the methylation panel, respectively. Median PFS (mPFS) was longer in pts with MR. Conclusions: Telisotuzumab adizutecan has promising efficacy. RRs were seen in CRC pts with heterogeneous genomic profiles, including pts positive for actionable biomarkers in the metastatic setting. More pts with MR experienced RRs and benefited from treatment. Clinical trial information: NCT05029882 . Pts with ctDNA and radiographic response data(N=113) Radiographic cPR, n/N (%) 20/113 (18) Genomic alteration TMB a high ( ≥ 20 mut/Mb) KRAS mut KRAS G12C mut BRAF mut b HER2 amp cPR, n/N (%) Pos 11/48 (23) 11/73 (15) 1/5 (20) 4/14 (29) 2/9 (22) Neg 9/51 (18) 9/40 (23) 19/108 (18) 16/99 (16) 18/104 (17) MR, n/N (%) 74-gene panel 42/66 (64) Methylation panel 48/74 (65) ORR, n/N (%) MR pos 15/42 (36) MR neg 2/24 (8) MR pos 17/48 (35) MR neg 0/26 (0) mPFS, mo (95% CI) Events (n/N) 6.1 (5.3, 6.9)28/42 3.5 (2.6, 4.3)21/24 5.9 (5.3, 6.8)31/48 3.5 (2.7, 4.1)23/26 MR in pts with SD, n/N (%) 74-gene panel 27/45 (60) Methylation panel 31/53 (58) mPFS, mo (95% CI)Events (n/N) MR pos 5.3 (4.5, 5.9)21/27 MR neg 3.9 (2.8, 4.3)16/18 MR pos 5.3 (4.5, 5.9)23/31 MR neg 4 (2.8, 4.4)19/22 a 14 pts not evaluable for TMB. Threshold determined by Guardant. b 1 pt had V600E mutation. mo, months; neg, negative; pos, positive.

Real world data of 177 Lutetium-PSMA-617 for metastatic castration resistant prostate cancer (mCRPC): Analysis of patients treated from 2 large reference centers.

e17050 Background: 177Lu-PSMA-617 was recently approved for the treatment of patients with mCRPC in the USA. While treatment is associated with improved survival, responses to therapy are lower in patients with visceral metastasis and with FDG avid disease. In this study, we aim to characterize response to the therapy trying to optimize patient selection for 177Lu-PSMA-617. Methods: Patients treated from 2020 to 2023 in 2 large oncology centers in Brazil were analyzed. Our primary endpoint was to investigate the PSA response rate. Secondary endpoints included overall survival (OS), time to next sequential therapies (TNST) and PSA response in patients with visceral disease. Patients were treated after being submitted to a double image consisting of PET-CT PSMA and a PET-CT FDG (as indicated by the TheraP trial, Hoffman et al.) confirming disease uptake without divergent disease. Results: A total of 32 patients with mCRPC were included in this analysis. The median age was 73 years. Median number of prior lines of therapy for mCRPC was 3 with 20 receiving more than one androgen receptor signaling inhibitor (ARSI) and 5 receiving more than one taxane. The percentage with a PSA response was 48,5% and visceral disease was present in 56,3% of patients. Response rate for pts with visceral disease versus non-visceral was 21,9% vs 43,8%. The Medians of TNST and OS were respectively 7 and 9,6 months. The characteristics of patients with and without a PSA response are detailed in the table. Conclusions: Our cohort, characterized by advanced age, extensive prior treatments, and elevated PSA values, exhibited a PSA response that aligns with patients treated in randomized trials. Notably, our patients with visceral disease demonstrated a lower PSA response. [Table: see text]

Valemetostat for Relapsed or Refractory B-Cell Lymphomas: Primary Results from a Phase 1 Trial

Introduction: B-cell non-Hodgkin lymphomas (B-NHLs), including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), are among the most common NHLs. Enhancer of zeste homolog (EZH)2 and EZH1 are methyltransferases that catalyze the trimethylation of histone H3 at lysine 27 (H3K27me3); this repressive transcriptional mark is broadly associated with gene silencing. EZH2 is involved in mediating B-cell development. Valemetostat tosylate (valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1. The clinical activity of valemetostat in patients (pts) with relapsed or refractory (R/R) NHL was investigated in the phase 1 DS3201-A-J101 (“J101”; NCT02732275) trial. Interim data were reported previously. Here we report primary clinical outcomes for the subgroup of pts in J101 with R/R B-NHLs, including DLBCL and FL. Methods: This phase 1, open-label, multicenter study was conducted in Japan and the United States (US). Eligible pts were aged ≥ 18 years (y; US) or ≥ 20 y (Japan), had confirmed B-NHL or T-cell NHL (T-NHL), and were relapsed from, refractory to, or ineligible for standard therapies. The trial included a dose-escalation portion (Japan only) followed by a dose-expansion phase (Japan & US). Pts with a histological diagnosis of B-NHL were enrolled in the dose-escalation phase and received valemetostat once daily at doses of 150-300 mg/day (d) in continuous 28-d treatment (Tx) cycles. Preliminary efficacy assessment included objective response rate (ORR), complete response (CR) rate, and duration of response (DOR). DOR was estimated for responding pts using Kaplan-Meier methods. Due to the small number of pts with B-NHL, safety was assessed among all enrolled pts, including those with T-NHL in the dose-escalation and dose-expansion cohorts. Results: At the primary trial cutoff (Dec 31, 2022), 19 pts with R/R B-NHLs were registered and had received ≥ 1 dose of study drug, including 7 with DLBCL, 7 with FL, 3 with indolent B-NHL, and 2 with other B-NHLs. Median age was 66 (range 44-88) y. Most (79%) pts had an Eastern Cooperative Oncology Group performance status score of 0. Median number of prior therapies was 2.0 (range 0-6); no pt in this cohort had received prior hematopoietic cell transplantation. Overall, 90 pts with R/R NHLs were enrolled. All pts experienced at least 1 treatment-emergent adverse event (TEAE), including 78 (87%) who had treatment-related TEAEs. The most common TEAEs (any grade) were decreased platelet count (64%), dysgeusia (50%), anemia (43%), decreased neutrophil count (34%), and alopecia (33%). The most common grade ≥ 3 TEAEs were cytopenias, including decreased neutrophil count (24%), platelet count (24%), and lymphocyte count (19%). TEAEs required Tx interruption for 42 (47%) pts, dose reduction for 9 (10%) pts, and Tx discontinuation for 7 (8%) pts. The overall response rate in pts with R/R B-NHL was 47% (9/19; 95% confidence interval [CI], 24.4-71.1). Clinical responses were seen in 3/7 pts with DLBCL and 4/7 pts with FL; 1 pt in each of these groups achieved CR ( Table). Of 19 pts, 9 (47%) achieved reductions of ≥ 50% from baseline in the sum of target lesion areas during valemetostat Tx ( Figure). A gain-of-function EZH2 mutation was identified in 1 pt with FL, and this pt achieved a partial response. Median time to response overall was 3.7 (range 1.9-10.1) months (mo) and estimated median DOR for the 9 responding pts was 18.4 mo (95% CI, 5.3 mo to not reached). Among all pts who received valemetostat 200 mg/d with pharmacokinetic (PK) data available (n = 74), mean [standard deviation; SD] maximum plasma concentration (C max) on cycle 1 day 1 was 2140 [1620] ng/mL, with a median time to C max (T max) of 3.9 (range 0.2-27.8) h and a mean [SD] AUC tau of 17,500 [21,400] ng × h/mL. Conclusions: Valemetostat demonstrated encouraging clinical activity in pts with R/R B-NHLs. The safety profile of valemetostat was acceptable; cytopenias were common but manageable and did not require Tx discontinuation between 150-300 mg/d. Clinical responses were durable, with a median DOR of > 1.5 y. Results for pts in this trial with R/R T-NHLs are presented in another abstract (Jacobsen et al.) at this congress. Ongoing trials of valemetostat in pts with R/R B-NHLs include a phase 2 monotherapy trial in France and Belgium (NCT04842877) and a phase 1/2 trial of valemetostat plus rituximab and lenalidomide (R 2) in the US (NCT05683171).

Molecular Determinants of Response to Mosunetuzumab Plus CHOP in Patients with Previously Untreated (1L) Diffuse Large B Cell Lymphoma (DLBCL)

Co-lead authors: Habib Hamidi and Patrick Kimes Background: Standard induction therapy cures ~60% of patients (pts) with DLBCL; however, most remaining non-responders die from lymphoma, highlighting a need for improved first-line treatments. Biomarkers that can reliably assess the efficacy of new treatments are lacking in clinical practice. Mosunetuzumab (Mosun) is a CD20xCD3 T cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. In a Phase Ib/II trial (NCT03677141), Mosun combined with CHOP chemotherapy (M-CHOP) induced high response rates in pts with 1L DLBCL (ORR 87.5%, CR 85%; Phillips et al. ASH 2020). Here, we sought to identify biomarkers associated with M-CHOP response. Methods: Pts with 1L DLBCL receiving M-CHOP (six cycles) in NCT03677141 and with available biomarker data were included. Bulk RNASeq data from pre-treatment tumor biopsies were analyzed using gene set variation for tumor intrinsic pathways and xCell cell-type enrichment for immune and stromal cell types. High or low expression of each gene signature was determined by median cut-off. Cox regression examined associations between gene signatures and PFS. To assess specificity to M-CHOP, gene signatures were examined in pre-treatment biopsies from pts treated with rituximab + CHOP chemotherapy (R-CHOP) in GOYA (NCT01287741; Sehn et al. J Hematol Oncol 2020). Peripheral blood biomarkers were evaluated by whole blood flow cytometry and plasma cytokines by ELISA. Circulating tumor (ct) DNA levels were measured at baseline and on treatment using the AVENIO NHL CAPP-Seq assay (Stokowski et al. ASH 2022). Results: In M-CHOP-treated pts (n=33), gene expression analysis revealed two types of signatures associated with PFS: tumor immune microenvironment signature (TIMS) and tumor intrinsic proliferation signature (TIPS; Figure). High TIMS expression (e.g., CD4+ T cells) was associated with significantly longer PFS than low expression. Conversely, pts with high TIPS expression (e.g., MYC targets, DNA repair) had shorter PFS than those with low expression. These biological associations were specific to M-CHOP and were not observed in R-CHOP-treated pts. Consistent with the tumor-gene expression analysis, immune profiling of peripheral blood suggested that in pts treated with M-CHOP, a higher T cell baseline count was associated with a trend for prolonged PFS compared with pts with a lower baseline count. A higher count of circulating suppressive T cells was also associated with shortened PFS. Early on-treatment pharmacodynamic (PD) changes were observed following the first Mosun dose, including: induction of TNFα and IL-6, transient margination of CD4+ and CD8+ T cells, and activation of CD4+ and CD8+ T cells. The magnitude of the PD effects were similar to observations with Mosun monotherapy in pts with relapsed or refractory DLBCL (Hernandez et al. ASH 2019), confirming that Mosun maintains its immune activation effect when combined with CHOP in pts with 1L DLBCL. High baseline ctDNA levels were associated with high IPI score (n=32, Wilcoxon rank-sum p=0.007), ABC/non-GCB DLBCL subtype (n=30, p=0.033), and high lactate dehydrogenase (n=32, p=0.004). Pts with baseline ctDNA levels < median had a modest trend for improved PFS compared with pts > median (unadjusted hazard ratio [HR]=0.57 [95% CI 0.16, 1.75]; IPI-adjusted HR=0.72 [95% CI 0.16, 3.20]). The proportion of pts with undetectable ctDNA increased with each M-CHOP cycle (C) (C2 day [D]1, 25% [8/32]; C3D1, 69% [20/29]; C5D1, 88% [22/25]). Pts with undetectable ctDNA at any on-treatment time point (C2D1, C3D1, C5D1) had superior PFS compared with pts with detectable ctDNA (unadjusted HR=0.12 [95% CI 0.03, 0.52]; IPI adjusted HR=0.14 [95% CI 0.03, 0.61]). Conclusions: Consistent with the Mosun mode of action, pts with high expression of TIMS and those with high levels of circulating T cells had improved PFS versus pts with low expression. In contrast, there was no association between immune cell signatures and PFS in pts treated with R-CHOP, suggesting that the different mode of action of rituximab versus Mosun may influence this. Future studies are warranted to confirm the potential clinical utility of immune cell signatures as biomarkers associated with CD20xCD3 bispecifics' activity.

Efficacy and safety of tunlametinib in patients with advanced NRAS-mutant melanoma: A multicenter, open-label, single-arm, phase 2 study.

9510 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085), a novel, potent, selective, oral small-molecule MEK1/2 inhibitor, has showed a favorable pharmacokinetics profile, acceptable tolerability and encouraging antitumor activity in the phase 1 study (BMC Med. 2023 Jan 4;21(1):2). Methods: This is an ongoing, multicenter, open-label, single-arm, phase 2 pivotal registration study. Patients (pts) with NRAS-mutant unresectable stage III or IV melanoma were enrolled and received tunlametinib 12 mg orally twice daily. A historical control of objective response rate (ORR) of 10% was predefined for sample size estimation (100 pts, assuming loss to follow-up rate of 5%) and efficacy evaluation. The primary endpoint was the confirmed ORR per RECIST v1.1 assessed by independent radiology review committee. Results: A total of 100 pts were enrolled. All pts were included in the safety analysis set and 95 pts were included in the full analysis set (FAS) for efficacy analysis. At cut-off date (August 17, 2022), median follow-up was 7.9 months (95% CI: 6.6, 9.8). In the FAS, the median age was 58.0 years (range: 24 to 84). Sixty-four pts (67.4%) had received prior immunotherapy (PD-1/PD-L1 inhibitor). Fifty-six pts (58.9%) were acral melanoma, 16 (16.8%) mucosal melanoma and 12 (12.6%) skin melanoma. Fourteen pts (14.7%) were stage III and 81 (85.3%) stage IV. The most frequent NRAS mutation types were Q61R (40.0%), Q61K (29.5%) and G12D (9.5%). Confirmed ORR was 34.7% (95%CI: 25.3%, 45.2%). Median progression-free survival was 4.2 months (95%CI: 3.5, 5.6), overall survival was immature, and 1-year survival rates was 57.2% (95% CI, 44.7%, 67.8%). Subgroup analysis showed that, in pts who had previously received immunotherapy, the confirmed ORR was 39.1% (95% CI: 27.1%, 52.1%). The most frequent treatment related adverse events (TRAEs) were increased blood creatine phosphokinase (CK), diarrhea, peripheral oedema, facial oedema and increased aspartate aminotransferase. Grade ≥3 TRAEs occurred in 68 pts (68.0%), of which 38.0% (38/100) were increased blood CK. Most of pts with CK elevation are asymptomatic and can be managed by dose interruption or reduction without permanent treatment discontinuation. No treatment-related death was reported. Conclusions: Tunlametinib was well tolerated and demonstrated encouraging treatment response rate in pts with advanced NRAS-mutant melanoma. These results indicate that tunlametinib could be a promising treatment option for NRAS-mutant melanoma, even for those immunotherapy failed pts. Clinical trial information: NCT05217303 .

AFT-50 EndoMAP: A phase IB/II multi-cohort study of targeted agents for patients with recurrent or persistent endometrial cancer.

TPS5634 Background: The prognosis for women with recurrent or persistent EC after progressing on first-line chemotherapy is poor, with a median overall survival (OS) of 12 months, highlighting the need for more efficacious therapies for this population. Immune checkpoint inhibitors either as monotherapy or when combined with kinase inhibitors have recently demonstrated encouraging response rates in pts with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Atezo is a humanized monoclonal anti-programmed cell death ligand 1 (PD-L1) inhibitor that has demonstrated monotherapy antitumor activity with an acceptable safety profile in relapsed recurrent EC. Atezo has shown compelling clinical efficacy for pts with certain solid tumors (e.g., urothelial, NSCLC, triple negative breast cancer) as monotherapy and as part of combinatorial therapy. The AFT-50 EndoMAP trial is a platform trial designed to evaluate the efficacy and safety of Atezo in combination with biomarker-defined targeted agents in pts with recurrent or persistent EC. Recognizing pts may have either progressed through or received a checkpoint inhibitor in a prior line of therapy, a non atezo cohort will also be open to enrollment. Methods: This is a phase IB/II non-randomized, multicenter, multicohort, biomarker-driven platform study consisting of two cohorts: A (atezo containing) and B (non atezo). Eligible pts have recurrent or persistent EC and have received no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In cohort A, pts may be eligible for one of the following doublets: Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered cancers), Atezo+talazoparib (tumors with genomic loss of heterozygosity (LOH) ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated and/or amplified tumors), Atezo+Tiragolumab (MSI-H and/or TMB>10 mut/MB), and Atezo+bevacizumab (biomarker unmatched). Pts will receive Atezo in addition to the targeted agent (at the study approved dosing schedule) until progression, unacceptable toxicity, pt or physician decision to withdraw from the study, death, or study termination. Pts in cohort B, will be eligible for inavolisib (PIK3CA/PTEN/AKT1-altered cancers) + letrozole. Each cohort will enroll ~20 pts; however, the exact size of the cohort may be adjusted. The primary endpoint for Cohort A is confirmed overall response rate (ORR) for each cohort, and for Cohort B is progression free survival at 6 months. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability, 6-month PFS (cohort A). As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 17 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .

Predictors of therapeutic efficacy of anamorelin in patients with gastric, pancreatic, and colorectal cancer.

331 Background: Anamorelin is a highly selective ghrelin receptor agonist that improves appetite and increases lean body mass in patients (pts) with cachexia. We aimed to investigate the predictors of therapeutic efficacy of anamorelin in pts with gastrointestinal cancer. Methods: This retrospective study included pts with gastric cancer (GC), pancreatic cancer (PC), and colorectal cancer (CRC) treated with anamorelin at our institution between May 2021 and July 2022. Glasgow Prognostic Score (GPS) was defined as follows: GPS 0: CRP≤1.0 (mg/dL) and Alb≥3.5 (g/dL), GPS 1: either CRP>1.0 or Alb<3.5, GPS 2: CRP>1.0 and Alb<3.5. The endpoints were the response rate (RR) of anamorelin and time to treatment failure (TTF). RR was defined as the proportion of appetite improvement within 3 weeks of anamorelin, and TTF was defined as the time from the start of anamorelin to discontinuation due to insufficient response. The observation period lasted 12 weeks. RR was analyzed by univariate and multivariate logistic regression analyses, and TTF by competing risk analysis. In the competing analysis, discontinuation of anamorelin due to worse symptoms, hospital transfer for poor condition, and adverse events (AEs) were considered as competing events. Results: A total of 103 pts were included; median age was 70 (range: 37–84) years, 61 pts (59%) were men, and 17 pts (17%) had an ECOG PS ≥2. The proportion of GC/PC/CRC were 43/42/16%; median body mass index (BMI) was 19.9 (range: 14.4–26.8) kg/m2. The treatment line for 1st/2nd/≥3rd/others was 51/13/14/22%, respectively. GPS was 0/1/2 in 21/30/49%, respectively. Except for treatment line, there were no significant differences in patient characteristics according to the cancer type. A total of 12 pts discontinued treatment owing to AEs (nausea, 3; epigastric distress, 2; fatigue, 2; poor physical condition, 2; staggering, 1; pulsation, 1; diarrhea, 1 pts). The RR was 42%. Pts with GPS 2 had less improvement in appetite than those with GPS 0 or 1 (26% vs. 56%, adjusted odds ratio [95% confidence interval (95%CI)]:0.22 [0.07–0.69], p=0.009). The RR of pts with GC, PC, and CRC were 44%, 42%, and 41%, respectively. The cumulative incidence of discontinuation of anamorelin after 12 weeks was higher in pts with GPS 2 than in those with GPS 0 or 1 (46% vs. 30%). The TTF in pts with GPS 2 was significantly shorter than that in pts with a GPS 0 or 1 (adjusted subdistributional hazard ratio [95%CI]:2.80 [1.37–5.72], p=0.005). There was no statistically significant difference in TTF by cancer type, although TTF was shorter in GC and PC than in CRC. Other factors, including age, sex, baseline BMI, ECOG PS, lines of therapy, and cancer type did not correlate with RR and TTF. Conclusions: In pts with a GPS of 0 or 1, anamorelin showed better appetite improvement and a longer treatment effect than in those with GPS 2. TTF was shorter in pts with GC and PC; therefore, the timing of use should be carefully considered.

HUMORAL IMMUNITY RESPONSES AFTER VACCINATION FOR HEPATITIS B VIRUS IN AUTOGRAFTED PATIENTS: A SINGLE CENTER EXPERIENCE

The effectiveness of vaccinations post hematopoietic stem cell transplantation (HSCT), is a reliable marker for immune system's functionality assessment. In autologous HSCT (AHSCT) setting, the general aspect is that the immune system recovers quite soon and patients (pts) are considered to be immunocompetent in a period of approximately 3-6 months post AHSCT. We evaluated the hepatitis B virus (HBV) vaccination responses in autografted pts who were in remission and off chemotherapy post AHSCT. 27 autografted pts aged 51,6 (22-67) ys, who had antiHbs titers <10 IU/ml before AHSCT and at the time of vaccination, were studied. After a successful engraftment the median absolute lymphocytes count at +3 months was 1740(450-4090)/mm 3 . In 4,3(0,6–8,5) ys post AHSCT, 3 doses of recombinant HBV vaccine were given monthly. The response rates for pts who completed 3 vaccine doses, compared with an internal group of healthy individuals, vaccinated in the same period with the same product. After the 1 st , 2 nd and 3 rd dose the response rates in the study group were 11%, 81% and 88% respectively. No factor statistically significantly influenced the achievement of protective antiHbs titers. The responses were lower as compared to product's efficacy profile (19%, 86% and 100% after the 1 st , 2 nd and 3 rd dose respectively), while in the comparative analysis with the internal control group, a trend for inferior responses in autografted pts was also noticed (88% vs 100%, p=0,07). This study, in a relatively homogenous group of pts, to our knowledge, is the only one that directly compares the HBV vaccine responses in autografted pts with healthy individuals. Although vaccination was offered late post AHSCT, the responses were lower compared to healthy individuals, indicating a possible long lasting immune impairment post AHSCT highlighting the necessity of prolonged surveillance and intensified vaccination programs for autografted pts.

P942: DREAMM-9: PHASE I STUDY OF BELANTAMAB MAFODOTIN PLUS STANDARD OF CARE IN PATIENTS WITH TRANSPLANT-INELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA

Background: The bortezomib, lenalidomide, and dexamethasone (VRd) regimen is a standard of care for newly diagnosed multiple myeloma (NDMM). Belantamab mafodotin (belamaf) is a B-cell maturation antigen-binding antibody-drug conjugate that eliminates myeloma cells by a multimodal mechanism: direct cell kill and anti-myeloma tumor immune response. Belamaf has demonstrated deep and durable responses as a monotherapy in the DREAMM-2 study of patients (pts) with relapsed/refractory multiple myeloma (RRMM). Preclinical evidence of belamaf in combination with bortezomib or lenalidomide suggests enhanced anti-myeloma activity, providing rationale for this treatment combination. Aims: To evaluate the safety and tolerability of this combination in adult pts with transplant-ineligible (TI) NDMM and establish the recommended Phase III dose. Methods: DREAMM-9 (NCT04091126) is an ongoing Phase I, open-label, randomized study of belamaf + VRd. The belamaf dose cohorts currently being evaluated are Cohort 1 (1.9 mg/kg Q3/4W), Cohort 2 (1.4 mg/kg Q6/8W), Cohort 3 (1.9 mg/kg Q6/8W), Cohort 4 (1.0 mg/kg Q3/4W), and Cohort 5 (1.4 mg/kg Q3/4W). Belamaf is given with VRd Q3W until Cycle 8, and with Rd Q4W thereafter. After evaluation of safety data for Cohort 1, Cohorts 2–5 were opened in parallel and enrolled pts were randomized 1:1:1:1. Primary endpoint is safety. Secondary endpoints include efficacy, tolerability, and pharmacokinetics (PK). Results: As of data cutoff (07 Dec 2021), 64 pts were analyzed across all cohorts. Median age (range) was 73.0 (51–88) years, 55% were male, 80% were white, 8% had extramedullary disease, 59% were International Staging System stage II or III, 20% had amp1q, and 17% had high-risk cytogenetics (≥1 of: t(4;14), t(14;16), del17p). The median duration of follow-up varied: Cohort 1 (17.4 months [mo]), Cohort 2 (5.9 mo), Cohort 3 (6.1 mo), Cohort 4 (4.7 mo), Cohort 5 (5.8 mo). Median number of belamaf cycles were: Cohort 1 (6), Cohort 2 (3), Cohort 3 (3.5), Cohort 4 (4.5), and Cohort 5 (5). Most common adverse events (AEs) across cohorts included thrombocytopenia (49%), constipation (43%), diarrhea (32%), and peripheral sensory neuropathy (30%). AEs related to study treatment were experienced by 61 (97%) pts. Belamaf-related grade 3/4 AEs occurred in 24 (38%) pts. Belamaf dose reductions occurred in 11 (18%) pts, with dose delays in 10 (16%) pts. Three pts experienced a fatal severe AE (unrelated to study treatment); 2 due to COVID-19 infection, 1 due to pancreatic adenocarcinoma. Early deep responses were observed; 67–92% pts achieved ≥very good partial response (VGPR) (Table), with median time to VGPR of 2.1–2.9 months across cohorts. Of pts with ≥VGPR, 17 were minimal residual disease (MRD) negative, 10 in Cohort 1. As of data cutoff, 8–75% of pts achieved best response of complete response (CR) or stringent CR (sCR). Grade 3 corneal exam findings were reported in 25–58% of pts; grade 3 visual acuity changes were reported in 21–75% of pts. No grade 4 corneal exam findings or visual acuity changes were reported in pts receiving belamaf Q6/8W, compared with 0–17% and 0–8%, respectively, in the Q3/4W cohorts. Belamaf PK profile was similar to that in pts with RRMM, accounting for baseline characteristics. Image:Summary/Conclusion: Belamaf + VRd demonstrated high response rates in pts with TI NDMM, with a high rate of MRD negativity indicating deep responses. No new safety signals were observed relative to DREAMM-2. Study is ongoing to evaluate the safety and efficacy of variable dose intensities of belamaf in combination with VRd.

Phase 2 Study of Zanubrutinib in BTK Inhibitor-Intolerant Patients (Pts) with Relapsed/Refractory B-Cell Malignancies

Phase 2 Study of Zanubrutinib in BTK Inhibitor-Intolerant Patients (Pts) with Relapsed/Refractory B-Cell Malignancies

Phase 2 March Study: ATG-010 Plus Low Dose Dexamethasone in Chinese Relapsed/Refractory Multiple Myeloma (RRMM) Patients Previously Treated with an Immunomodulatory Agent (IMiD) and a Proteasome Inhibitor (PI)

Background:ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, which blocks exportin 1. US FDA has approved selinexor plus low dose dexamethasone (Sd) to treat patients (pts) with penta-refractory MM based on the STORM study. MARCH is a single arm, Phase 2, registrational study to assess efficacy and safety of Sd in Chinese pts with RRMM.Methods:Enrolled Chinese pts were previously refractory to PI, IMiD, and last line of therapy. ATG-010 (80mg) plus dexamethasone (20mg) was administered twice weekly. The primary endpoint was overall response rate (ORR) per independent review committee. The planned 82 pts would provide ~80% power to test against null hypothesis (H 0) of 15% ORR at one-sided α of 0.025 at the primary analysis, which is presented here.Results:As of 6 th May 2021, 9 (11%) of the 82 pts were still on treatment. Median follow-up was 10.6 months (mo) (range: 2.3-19.6).Median age was 60 years (39% ≥ 65yrs). Median duration from MM initial diagnosis was 3.2 years. A total of 61 pts (74.4%) had cytogenetic abnormalities (del(17p): 22.0%), 18 (22.0%) with baseline plasmacytoma, and 18 (22.0%) with creatinine clearance < 60ml/min. Median number of prior regimens were 5 (range 1-16); 23 pts (28.0%) had received daratumumab (triple-class exposure), 20 pts were triple-class refractory (TCR), and10 pts (12.2%) had undergone CAR-T therapy.ORR was 29.3% (95% CI: 19.7, 40.4), rejecting H 0, including 4 VGPR (very good partial response). Median duration of response (DOR) was 4.7 mo, median progression free survival (PFS) was 3.7 mo, and median overall survival (OS) was 13.2 mo.Among 20 TCR pts, ORR was 25.0% (95% CI:8.7, 49.1), mDOR 10.2 mo, mPFS 2.9 mo, and mOS 11.9 mo.Efficacy was evident in elderly pts (≥ 65yrs), with ORR 25% (95% CI: 11.5, 43.4) and mPFS 2.8 mo. Median OS and DOR were not reached.Sd also demonstrated a similar response rate in pts with high-risk cytogenetic abnormalities, with an ORR of 24.6% (95% CI: 14.5, 37.3). Efficacy of Sd was generally consistent across cytogenetic risk subgroups, including del (17p) pts with ORR 22.2% (95% CI: 6.4, 47.6), mDOR 3.8mo, and mPFS 2.9 mo.The most common non-hematologic treatment-emergent adverse events (TEAEs) of any grade included nausea (78%), hyponatremia (67.1%), weight loss (65.9%), decreased appetite (62.2%), asthenia (59.8%)/fatigue (15.9%), and vomiting (50.0%). The most common grade≥3 non-hematologic TEAE were hyponatremia (29.3%), pneumonia (26.8%), hypokalemia (12.2%) and asthenia (9.8%)/fatigue (2.4%). The most common grade≥3 hematologic TEAEs were anemia (57.3%), lymphopenia (76.8%), thrombocytopenia (51.2%), and neutropenia (40.2%). TESAE occurred in 54.9% of pts, with the most common being thrombocytopenia and pneumonia (14.6% each). TEAE led to death in 7 pts (8.5%). Elderly pts had no significantly increased risk of adverse events, however, given their limited physical state, drug exposure was shorter in the elderly subgroup (12.6 vs 16.1 weeks), suggesting more active supportive care is required.Conclusions:MM refractory to both IMiD and PI remains a high unmet medical need, especially in China. The MARCH study demonstrates statistically significant and clinically meaningful ORR with Sd in Chinese RRMM pts, and efficacy was consistent across subgroups, including the elderly and pts with high-risk cytogenetics. Adverse events were as expected and manageable with appropriate supportive care and dose modification. These data are compatible with the STORM study and offers a new, oral therapeutic option for MM patients. DisclosuresYu: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Yang: Antengene Therapeutics Ltd.: Current Employment. Yu: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.

Glofitamab As Monotherapy and in Combination with Obinutuzumab Induces High Complete Response Rates in Patients (pts) with Multiple Relapsed or Refractory (R/R) Follicular Lymphoma (FL)

Glofitamab As Monotherapy and in Combination with Obinutuzumab Induces High Complete Response Rates in Patients (pts) with Multiple Relapsed or Refractory (R/R) Follicular Lymphoma (FL)

Glofitamab Step-up Dosing Induces High Response Rates in Patients (pts) with Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL), Most of Whom Had Failed Prior Bruton's Tyrosine Kinase Inhibitor (BTKi) Therapy

Glofitamab Step-up Dosing Induces High Response Rates in Patients (pts) with Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL), Most of Whom Had Failed Prior Bruton's Tyrosine Kinase Inhibitor (BTKi) Therapy

Molecular Characteristics of Response to Olutasidenib (FT-2102) in Patients with Relapsed/Refractory mIDH1 Acute Myeloid Leukemia

Molecular Characteristics of Response to Olutasidenib (FT-2102) in Patients with Relapsed/Refractory mIDH1 Acute Myeloid Leukemia

Clinical Characteristics and Outcomes of AML Patients Treated with Frontline CPX 351 or HMA/Venetoclax: A Single Institution's Experience

Introduction: Treatment options for newly diagnosed patients (pts) with acute myeloid leukemia (AML) have historically been limited. The combination of a hypomethylating agent and venetoclax (HMA/Ven) has emerged as standard of care treatment for elderly and/or unfit pts with newly diagnosed AML. Liposomal cytarabine/daunorubicin (CPX-351) has also become standard of care therapy for pts with AML with myelodysplasia related changes or therapy-related AML. Despite being an intensive regimen, CPX-351 may have a more favorable toxicity profile compared to other intensive regimens. As a result, CPX-351 may be offered to older fit pts who may not have been candidates for traditional induction regimens. As the landscape for frontline treatment options evolves, there are now overlapping pt populations who may be eligible for either frontline treatment option. A retrospective study that included clinical trial pts demonstrated similar response rates in pts treated with HMA/Ven and CPX-351 (Asghari Blood 2019). Similarly, a study of secondary AML pts receiving HMA/Ven and CPX-351 showed no difference in remission rate or survival (Salhotra Am J Hematol 2021). There remains a shortage of data describing clinical characteristics of pts selected for and treated with standard-of-care HMA/Ven and CPX-351. We present a study on our center's experience.Methods: The purpose of this study was to evaluate the clinical characteristics and outcomes of adult pts with newly diagnosed AML who were treated with either CPX-351 or HMA/Ven as initial therapy. Consecutive pts treated with either of these two induction therapies between August 2017 and June 2021 were evaluated retrospectively. Pts were eligible for response evaluation if they received at least 3 doses of CPX-351 or 28 days (1 cycle) of venetoclax (“response cohort”). All pts treated with CPX-351 or HMA/Ven were included in survival analysis (“survival cohort”). Response assessment is based on ELN-2017 criteria. Pt characteristics were described and compared using Fisher's Exact tests. Kaplan-Meier methods were used to summarize overall survival, and log-rank tests were used for the comparison of frontline therapies. Cox proportional-hazards regression estimated hazard ratio (HR), 95% confidence interval (CI), and interactions between frontline therapy and age at induction start.Results: A total of 79 pts were identified receiving frontline HMA/Ven or CPX-351; 61 pts (77%) were evaluable for response. Of the response cohort, 21 (34%) were treated with CPX-351 and 40 (66%) with HMA/Ven; pt characteristics are described in Table 1. CPX-351 pts were younger at start of induction (P<0.001); many pts in both treatment groups had unfavorable ELN risk scores at diagnosis (CPX 43%, HMA/Ven 41%; P>0.99). 33% and 23% of the HMA/Ven cohort achieved CR and CRi respectively; in the CPX-351 cohort 57% and 5% achieved CR and CRi respectively. A greater fraction of CPX-351 pts proceeded to allogeneic stem cell transplant than HMA/Ven pts (67% vs 23%; P<0.001). No differences were detected in achievement of MRD negativity by flow cytometry (P=0.51) or molecular profile (P=0.52).Median follow-up for all pts was 18.9 months; 42 deaths occurred. Differences in survival between the frontline therapies were not detected in the survival cohort (HR, 1.31; 95% CI, 0.67 to 2.57; P=0.43) nor the response cohort (HR, 0.97; 95% CI, 0.45 to 2.09; P=0.93); these results were unaffected by adjustments for age at induction, ELN risk score, and transplant status.8 pts who initially received CPX-351 and had refractory disease later went on to receive HMA/Ven reinduction; 2 achieved CRi, 2 MLFS, 3 Refractory and 1 Death in Aplasia. 1 pt who initially received HMA/Ven with refractory disease went on to receive CPX-351. This pt was refractory to CPX-351.Conclusion: HMA/Ven and CPX-351 are effective frontline treatment options with similar response rates and survival outcomes in newly diagnosed adults with AML. Pts treated with CPX-351 were younger and more likely to proceed with allogeneic transplantation, in line with standard practice. Though there was heterogeneity in pt populations, age did not appear to affect outcomes. As the landscape for standard-of-care upfront treatment for AML continues to evolve, further studies are warranted to determine optimal therapy selection and sequencing. [Display omitted] DisclosuresArnall: Novo Nordisk: Speakers Bureau. Symanowski: Carsgen: Consultancy; Immatics: Consultancy, Other: DSMB Member; Eli Lilly: Consultancy, Other: DSMB Member. Avalos: JUNO: Membership on an entity's Board of Directors or advisory committees. Copelan: Amgen: Consultancy. Grunwald: Cardinal Health: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Agios: Consultancy; Janssen: Research Funding; PRIME: Other; Karius: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Blueprint Medicines: Consultancy; Gilead: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy; Med Learning Group: Other; Sierra Oncology: Consultancy; MDEdge: Other; PER: Other; Trovagene: Consultancy; Stemline: Consultancy.

Atezolizumab Combined with Immunogenic Salvage Chemoimmunotherapy (R-GemOx+Atezo) in Patients with Transformed Diffuse Large B-Cell Lymphoma

Atezolizumab Combined with Immunogenic Salvage Chemoimmunotherapy (R-GemOx+Atezo) in Patients with Transformed Diffuse Large B-Cell Lymphoma

Omacetaxine Mepesuccinate for Patients with Higher-Risk MDS and CMML after Failure of Hypomethylating Agents: A Phase II Trial

Background: The outcome of patients (pts) with myelodysplastic syndromes (MDS) after hypomethylating agent (HMA) failure is poor with a median survival of 4-6 months. Omacetaxine mepesuccinate (OM) has been shown to be safe and effective in acute myeloid leukemia, including in pts who progressed from MDS. We designed a phase II trial to evaluate the safety and efficacy of OM in pts with MDS and chronic myelomonocytic leukemia (CMML) after HMA failure.Methods: Adult pts with MDS or CMML who had not responded to, progressed on, or relapsed after HMA therapy were eligible for this study. Pts were required to be intermediate-2- or high-risk by the International Prognostic Scoring System (IPSS) or be classified as RAEB-1 (5-9% BM blasts), RAEB-2 (10-19% BM blasts) or CMML (5-19% BM blasts). Pts received OM 1.25 mg/m2 SQ every 12 hours x 3 days on a 28-day cycle. The primary efficacy outcomes were overall survival (OS) and the overall response rate (ORR). Secondary outcomes included the remission duration, relapse-free survival (RFS), and the safety of the regimen.Results: Between 6/2015 and 6/2017, 35 pts have been treated. Baseline characteristics are shown in Table 1. The median age of the cohort was 73 years (range, 61-86 years). The median BM blasts was 10% (range, 2-19%) and 15 pts (43%) had poor-risk karyotype. IPSS risk group was intermediate-1 in 8 pts (23%), intermediate-2 in 13 (57%), and high in 7 (20%). 27 pts (77%) were either high risk (n=10) or very high risk (n=17) by IPSS-R. Among 33 pts who underwent comprehensive mutation profiling, 29 (88%) had at least one mutation identified. The most frequently identified mutations were RUNX1 in 10 pts (30%), TP53 in 10 (30%), ASXL1 in 6 (18%) and TET2 in 4 (12%).The median duration of follow-up was 17 months (range, 2-24 months), and the median number of cycles of OM received was 2 (range, 1-18). The ORR was 34%; 3 pts achieved CRp and 9 pts achieved CRi as best response. The median number of cycles to best response was 2 (range, 1-4 cycles). The response rates for pts with MDS and CMML were 41% and 0%, respectively (P=0.02). Responses were seen across cytogenetic risk groups: 5 responders were diploid, 4 had either complex cytogenetics or monosomy 7, and 3 had miscellaneous cytogenetic abnormalities. The response rate for pts with diploid and adverse-risk cytogenetics were 56% (5/9) and 27% (4/15), respectively (P=0.16).Of the 12 responders, 4 remain on study, 5 relapsed, 2 died while in response, and 1 was lost to follow-up. To date, 24 pts (69%) have died. The median OS was 7.6 months, and the 1-year OS rate was 22% (Figure 1). The median RFS was 2.9 months, and the 1-year RFS rate was 28%. Two pts have had ongoing response ≥12 months (15.6 and 19.8 months), both of whom had MDS with diploid cytogenetics.Treatment was overall well-tolerated. Among 26 pts who have received ≥2 cycles of OM, 2 (8%) required dose reduction during subsequent cycles. Most adverse events were grade 1-2; grade ≥3 adverse events occurred in 8 pts (23%). The most frequent non-hematologic adverse events were fatigue in 17 pts (49%), nausea in 12 (34%), mouth sores or mucositis in 6 (17%), infection in 5 (14%) and edema in 5 (14%). The 30-day and 60-day mortality rates were 11% and 14%, respectively.Conclusions: In pts with MDS and CMML who previously failed HMA therapy, OM was safe and resulted in an ORR of 34%. Responses were seen across cytogenetic risk groups but were restricted to patients with MDS. [Display omitted] DisclosuresTakahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Bose:Incyte Corporation: Honoraria. Cortes:BMS: Consultancy, Research Funding; Teva: Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Amgen: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy.

Long-Term Outcomes in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Long-Term Outcomes in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Barriers to Successful Implementation of Precision Medicine to the Treatment of Refractory AML: Lessons Learned

Tremendous genomic heterogeneity has been reported for patients with acute myeloid leukemia (AML), as well as variability in gene expression. We have developed a custom high throughput drug sensitivity (HTS) assay enabling testing of ~150 drugs and combinations, both FDA approved and investigational, including chemotherapy agents and targeted inhibitors. We enrolled advanced relapsed/refractory AML patients (pts) on two successive trials, NCT01872819 “Treatment for Relapsed / Refractory AML Based on a High Throughput Drug Sensitivity Assay” and NCT NCT02551718 “Individualized Treatment for Relapsed/Refractory Acute Leukemia Based on Chemosensitivity and Genomics/Gene Expression Data.” The first trial enrolled 16 AML pts (3-5 prior regimens) of whom 14 received single agent study directed treatment, and the second trial (2-6 prior regimens) enrolled 25 AML pts of whom 14 received study directed therapy including drug combinations. We were able to choose chemotherapy drugs for all pts that had IC50's of ≤ 0.1 µM, or regimens that demonstrated synergy for drugs in combination. We have established feasibility as defined by the study, in that HTS assay results were reported at an average of 5.6 days (range 4-10), mutation analysis for 194 genes by MyAML™ reported in 12.5 days (range 9-17) with turnaround from receipt median 8 days (range 7-12) and treatment started at 7.8 (mean), 8 (median) days (range 4-11).In the first trial, 1 pt (5prior regimens), achieved complete remission with incomplete count recovery (CRi) with the single chosen drug, and 1 achieved CR, 1 CRi with subsequent regimens of additional drugs based on screening and published combinations. Median overall survival (OS) was 88 days for all patients, range 7 to 411. For the 2nd trial, where combinations were used, there were 2 CRs, 1 CRi and 3 partial responses. Median OS was 122 days, range 19-379. Of the patients in the 1st trial who had therapy that could have been directed by mutation analysis, there were 4 with FLT3, 1 KIT, 1 IDH2, 1 TP53, 1 FLT3+KIT, 2 FLT3+ IDH2 mutations (10/12 tested). For the 2nd trial there were 2 pts with FLT3D835, 2 TP53, 2 translocations involving FLT3, 1 IDH2 + FLT3-ITD, 1 FLT3-ITD + IDH1, 1 IDH1, 1 FLT3D839, 1 FLT3-ITD + TP53, 1 IDH2, 1 BCR-ABL (13/17 tested), and one patient received imatinib for BCR-ABL, 2 sorafenib for Flt3 mutations, and 1 with a TP53 mutation received decitabine. We had a number of logistical difficulties, including very advanced disease , poor performance status, inability to obtain the drugs with the lowest IC50's or as directed by mutations due to investigational status or lack of insurance approval, and inability to treat pts who returned home to their local physicians. We observed a higher response rate in pts who received drug combinations (8) vs. single agents (1). Although these were just feasibility trials, we also tried to compare their outcomes to a historical control group. We selected 2 matches for each of our pts, total of 50. They were matched to age, length of CR1, prior HCT, prior intense salvage and prior number of total salvages. One limitation was to find controls that had received ≥3 salvages like some of our studied population. Most of the patients in our clinical trial received single drug therapy (64 vs 24%) and non-intense therapy (4 vs 44%), when compared to our historical control group. Although these were very important treatment differences, the median OS did not differ statistically between both groups (88 vs 115 days, p: 0.327).We have gathered clinical data, and data on mutation analysis, gene expression, and drug sensitivity testing, that have been analyzed to determine correlations of specific features with drug resistance. Moreover, we have the ability to confirm functional drug sensitivity to the targeted inhibitors based on mutation data. All these data can contribute to future algorithms to assist in optimizing drug choices.In conclusion, our future iterations of this approach will include 1) only drug combinations, 2) study of pts with only 2 prior regimens, and 3) earlier incorporation of targeted inhibitors such as midostaurin and the new IDH2 inhibitor, enasidenib, into combination regimens. The current salvage options for relapsed/refractory AML have dismal results, as exhibited by our historical control group; only 10% were alive at 1 year. We will therefore pursue alternative approaches for this population, including the optimization of precision medicine methodology. DisclosuresWalter:ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding. Patay:Invivoscribe: Employment. Carson:Invivoscribe, Inc.: Employment. Radich:Amgen: Consultancy; Gilliad: Consultancy; Novartis: Consultancy, Other: lab contracts for bid and service assays; BMS: Consultancy; Ariad: Consultancy; Pfizer: Consultancy. Becker:GlycoMimetics, Inc.: Research Funding.

CC-122, a Novel Cereblon Modulating Agent, in Combination with Obinutuzumab (GA101) in Patients with Relapsed and Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL)

Introduction: Patients (pts) with R/R NHL, including follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) have a poor prognosis with limited 2L and 3L treatment options (MacDonald et al. Curr Oncol 2016). Early relapse (ER) pts with FL experiencing progression within 2 years of initial diagnosis and those double refractory (DR) to both rituximab and chemotherapy have particularly poor outcomes (Casulo et al. J Clin Oncol 2015; Gopal et al. N Eng J Med 2014). CC-122 is a novel oral agent that binds the cereblon ubiquitin ligase complex, resulting in degradation of the hematopoietic transcription factors Aiolos and Ikaros. Preliminary results from CC-122-NHL-001, a phase Ib study of CC-122 in combination with obinutuzumab, have shown promising response rates in pts with R/R B-cell NHL (Michot et al. ASH 2016). Herein, we report updated results for safety and efficacy from CC-122-NHL-001 (NCT02417285) with further 12 months follow up. Methods: Eligible pts age ≥18 years had histologically or cytologically confirmed CD20+ B-cell R/R NHL after ≥1 prior regimen for FL/marginal zone lymphoma (MZL) or after ≥2 regimens and/or autologous stem cell transplant (ASCT) for DLBCL. CC-122 was given orally (5 of 7 d) for 28-d cycles in escalating doses plus a fixed dose of intravenous obinutuzumab 1000 mg on d2, 8, 15 of cycle 1 (c1), and d1 of c2-8, upon informed consent. CC-122 active ingredient in capsule formulation (AIC) 1, 2, 3, and 4 mg and CC-122 formulated capsules (F6) 3 and 4 mg were evaluated in separate cohorts. Primary endpoints included safety and tolerability, non-tolerated dose (NTD), and maximum-tolerated dose (MTD). Response was assessed using the Cheson 2007 criteria every 2 cycles to c6, every 3 cycles to c12, and every 6 cycles thereafter. Results: As of May 1, 2017, 38 pts with R/R B-cell NHL were enrolled in the dose-escalation phase of the study. Tumor types included 19 pts with DLBCL, 18 with FL, and 1 with MZL. Of the 18 pts with FL, 10 (5 DR+ER and 5 ER) were difficult to treat, high-risk pts. Median age was 60 years (range, 26-81), 26 (68%) were male, and 29 (76%) had stage III/IV disease. Of the 19 pts with DLBCL, 8 (42%) had transformed DLBCL, and of the 19 pts with FL/MZL, 8 (42%) relapsed in 1 pt. Three deaths occurred during the study (2 PD; 1 AE-related, tumor flare). Median duration of CC-122 treatment was 23.6 weeks (range, 3.4-87.0), equivalent to 7 cycles (range, 1-22). CC-122 dose reduction or temporary interruption occurred in 12 (32%, all due to AEs) or 32 (84%, 26 due to AEs) pts, respectively. Fifty-five percent of pts had Conclusions: The novel, chemotherapy-free combination of CC-122 and obinutuzumab was well tolerated with promising response rates, and durable remissions in R/R B-cell NHL. The safety profile was consistent with other studies of CC-122, with AEs being mainly hematological and manageable. Notably, subgroup analysis showed that the combination has similar efficacy in the high-risk ER and DR subgroups of RR FL compared with the overall FL population. A CC-122 dose of ≥3 mg with obinutuzumab shows the best response rates to date, with deep response upon prolonged treatment. Expansion part B is currently on-going in both lenalidomide naive and lenalidomide refractory FL pts. Disclosures Doorduijn: Celgene: Honoraria; Roche: Honoraria. Vitolo: Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Honoraria; Takeda: Honoraria; Mundipharma: Honoraria. Kersten: Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Milennium/Takeda: Honoraria, Research Funding; Mundipharma: Honoraria; Gilead Sciences: Honoraria; BMS: Honoraria; Kite Pharma: Honoraria; Amgen: Honoraria; MSD: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria. Chiappella: Teva: Speakers Bureau; Roche: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Nanostring: Speakers Bureau; Pfizer: Speakers Bureau. Zinzani: Celgene, Janssen, Gilead, Roche, Takeda, BMS, MSD, Sandoz, Servier, Mundipharma: Speakers Bureau; Merck: Consultancy, Other: Advisory board; ​Celgene, Roche, Janssen, Gilead, Takeda, BMS, MSD, Servier, Sandoz, Mundipharma: Honoraria. Sarmiento: Celgene Research S.L.: Employment, Equity Ownership. Mosulen: Celgene Institute for Translational Research Europe: Employment. Mendez: Celgene Institute for Translational Research Europe: Employment. Petrarca: Celgene Corporation: Employment, Equity Ownership. Pourdehnad: Celgene Corporation: Employment, Equity Ownership. Hege: Celgene Corporation: Employment, Equity Ownership. Li: Celgene Corp.: Employment. Nikolova: Celgene International Sarl: Employment, Equity Ownership. Ribrag: Epizyme: Honoraria; BMS: Honoraria; MSD: Honoraria; Infinity: Honoraria; Gilead: Honoraria; Nanostring: Honoraria; Roche: Honoraria; ArgenX: Research Funding; Servier: Consultancy, Honoraria.