Overall Response Rate Rate Research Articles

Epcoritamab SC Monotherapy Leads to Deep and Durable Responses in Patients with Relapsed or Refractory Follicular Lymphoma: First Data Disclosure from the Epcore NHL-1 Follicular Lymphoma Dose-Expansion Cohort

Background: Despite recent therapeutic advances, an unmet need exists for efficacious, well-tolerated, and convenient treatment (tx) options for patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL). In particular, pts with high-risk disease, including those refractory to both anti-CD20 tx and an alkylating agent (double refractory) and those with disease progression within 2 y of first-line (1L) immunochemotherapy (POD24), require more effective options. Epcoritamab, a subcutaneous (SC) CD3xCD20 bispecific antibody, was recently approved by the US FDA for the tx of adults with R/R diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic tx. Here we present initial results from the FL dose-expansion cohort of the EPCORE™ NHL-1 trial (NCT03625037; phase 1/2). Methods: Pts with CD20 + R/R FL (grade [G] 1-3A) who had received ≥2 prior lines of systemic tx received epcoritamab SC in step-up doses (SUD 1 and 2) in cycle (C) 1, followed by full doses of 48 mg in 28-d Cs: QW, C1-3; Q2W, C4-9; and Q4W, C≥10 until disease progression or unacceptable toxicity. The primary endpoint of overall response rate (ORR) was assessed per Lugano criteria by an independent review committee. As a secondary analysis, minimal residual disease (MRD) was assessed in peripheral blood using the clonoSEQ ® assay (Adaptive Biotechnologies, Seattle, WA). Results: Between Sep 2020 and Oct 2022, 128 pts with R/R FL G1-3A were enrolled to receive epcoritamab SC. As of Apr 21, 2023, the median follow-up was 17.4 mo. Median age was 65 y, 61% of pts had FLIPI 3-5, and 85% had stage III-IV disease. The median number of prior lines of tx was 3 (range, 2-9); 31% of pts had ≥4 prior lines of tx. Common prior therapies included anthracyclines (77%), lenalidomide (31%), and autologous stem cell transplant (19%). Most pts were primary refractory (54%), double refractory (70%), or refractory to their last prior tx (69%); 42% had POD24, and 52% progressed within 2 y of initiating any 1L tx. The ORR was 82%, with a complete response (CR) rate of 63% ( Figure). The median time to response and CR was 1.4 and 1.5 mo, respectively. ORRs/CR rates were generally consistent across prespecified high-risk subgroups: double refractory, 76%/56%; refractory to last prior tx, 74%/51%; POD24, 80%/61%; progression within 2 y of initiating any 1L tx, 79%/64%. High ORRs/CR rates were observed across lines of tx, with a trend of higher rates in earlier lines: 2 prior lines, 89%/72%; 3 prior lines, 88%/68%; ≥4 prior lines, 68%/45%. Median progression-free survival (PFS) was 15.4 mo; median duration of response, duration of CR, and overall survival were not reached. An estimated 85% and 74% of pts with CR remained in response at 12 and 18 mo, respectively. MRD negativity was correlated with improved PFS. The most common tx-emergent AEs (TEAEs) of any grade were CRS (66%), injection-site reaction (57%), COVID-19 (40%), fatigue (30%), neutropenia (28%), diarrhea (27%), and pyrexia (25%). TEAEs leading to tx discontinuation occurred in 19% of pts, the most common being COVID-19. CRS was mostly low grade (40% G1, 25% G2, 2% G3) and primarily occurred following the first full dose (median time to onset after first full dose, 15 h). No CRS events led to tx discontinuation. ICANS was reported in 8 pts (6% overall; 4% G1, 2% G2); all resolved without leading to tx discontinuation. Fatal TEAEs occurred in 13 pts (10%). In a separate R/R FL cohort evaluating an optimized SUD regimen in C1 to mitigate CRS risk, a clinically meaningful reduction in CRS incidence and severity was observed (data to be presented). Conclusions: Single-agent epcoritamab SC resulted in deep and durable responses with high ORR and CR rates in hard-to-treat, high-risk pts with R/R FL. Responses were consistent across subgroups. A correlation between MRD negativity and PFS was observed. The safety profile was manageable; CRS occurrence was predictable, and a reduction in CRS occurrence and severity was seen with an optimized SUD regimen. Overall, no new safety signals were detected. Epcoritamab is currently being investigated in several FL trials across lines of tx, including an ongoing phase 3 trial (NCT05409066) in R/R FL.

C-CAR039, a Novel Anti-CD20/CD19 Bi-Specific CAR T-Cell Therapy Shows Deep and Durable Clinical Benefits in Patients with Relapsed or Refractory (r/r) B-Cell Non-Hodgkin Lymphoma (B-NHL) in Long Term Follow up

Background: We previously reported that C-CAR039, an autologous anti-CD20/CD19 bispecific chimeric antigen receptor (CAR) T-cell therapy, demonstrated a favorable safety profile and promising efficacy in patients (pts) with r/r B-NHL. Of the initial 28 pts treated with C-CAR039 with a median of 3 prior lines of therapy. Only 1 patient experienced grade ≥3 cytokine release syndrome (CRS), and no patient reported grade ≥2 immune effector cell-associated neurotoxicity syndrome (ICANS). The overall response rate (ORR) was at 92.6%, with 85.2% complete response (CR). After a median follow-up of 7 months, 74.1% of pts remained in CR, and the Kaplan-Meier (KM) estimation of progression-free survival (PFS) at 6 months was 83.2%. (Liang et al. ASCO 2021. #2507). Here we present the updated results to include more pts (48 pts) and a longer duration of follow-up (median 23.9 months). Methods: This is an open-label, dose escalation and expansion investigator-initiated trial (IIT) of C-CAR039. This trial was conducted at 4 sites to determine the safety and efficacy of C-CAR039 in pts with r/r B-NHL. Pts with r/r diffuse large B cell lymphoma (DLBCL), primary mediastinal large B cell lymphoma (PMBCL), follicular lymphoma (FL) or mantle cell lymphoma (MCL) were enrolled and received a single C-CAR039 infusion at a dose of 1.0-5.0x10 6 CAR-T cells/kg after a 3-day conditioning chemotherapy. The primary objective was to assess the safety and tolerability. CRS and ICANS were graded according to ASTCT 2019 criteria. The secondary objectives were to evaluate C-CAR039 efficacy and pharmacokinetics. Response was assessed per Lugano 2014 criteria. Results: Between Nov 5, 2019, and Jan 11, 2022, 48 pts received C-CAR039 manufactured using Miltenyi Biotec CliniMACS Prodigy® System. Of the 48 pts, 44 pts had large B-Cell Lymphoma (LBCL) (DLBCL, n = 37; PMBCL, n = 3; tFL, n=4), 3 pts had FL and 1 patient had MCL. The median age was 55 (range, 25-71) years, and 11 (22.9%) pts were ≥ 65 years. Thirty-six (75%) pts were in Ann Arbor Stage III/IV with 3 median prior lines of therapy (range, 1-7). All pts received anti-CD20 antibody and alkylating agents. Eight (16.7%) pts had prior ASCT, 32 (66.7%) pts were refractory to their last treatment, and 22 (45.8%) pts never achieved CR to their prior therapies. Prior to C-CAR039 infusion, 12 (25%) pts received bridging therapy. As of Jan 15, 2023, 45 pts (93.8%) experienced CRS, of which 44 (91.7%) pts reported grade 1 or 2, only 1 (2.1%) patient experienced grade 3 CRS. Median time to CRS onset was 3 days (range, 1-12), with median duration of 5 days (range, 2-78). Three pts had ICANS at a dose of 5.0x10 6 CAR-T cells/kg, of which 2 were grade 1 and 1 was grade 2. The median time to onset of ICANS was 6 days (range, 5-29), with a median duration of 12 days (range, 3-53). All CRS and ICANS were resolved. Grade ≥3 neutropenia, anemia, thrombocytopenia and infection were reported in 83.3%, 14.6%, 27.1% and 10.4% of pts, respectively. Second primary malignancy after C-CAR039 infusion were observed in 3 pts; 2 acute myeloid leukemia (AML) occurred at 2 and 10 months, and 1 Epstein-Barr virus-positive cytotoxic T-cell lymphoma was at 8 months, the tumor biopsy was tested with qPCR and CAR transgene was negative and none were related to C-CAR039. Twelve deaths occurred, 9 due to disease progression, 2 due to AE of AML, and 1 due to unknown cause. Of the 48 pts, 47 pts were evaluable for efficacy (1 patient with DLBCL had no measurable disease at baseline). The ORR and CR rate among evaluable pts were 91.5% and 85.1% respectively. Median time to first response and CR was 1.0 month (range, 0.9-1.9) and 1.1 month (range, 0.9-8.9), respectively. Of the 43 LBCL pts, the ORR was 90.7%, with 86.0% CR. Median DOR, PFS and OS were not reached. The KM estimation of PFS and OS rate at 24 months was 66.0% (95%CI 53.2%-81.9%) and 77.9% (95% CI, 66.6%-91.1%) respectively. C-CAR039 showed cellular kinetic profile consistent with commercial CAR-T therapies. In 48 evaluable pts, the median T max was 11.5 day (range, 7-31), the median C max was 139,416 copies/g gDNA (range, 708-962,445), and the median AUC 0-28day was 1,513,442 copies/ug∙day (range, 3,818-11,594,912.5). Conclusions: At a longer median follow-up of 23.9 months, C-CAR039 demonstrated a favorable safety profile with deep and durable response in pts with r/r B-NHL, especially in LBCL pts.

Efficacy and Safety of Idecabtagene Vicleucel (ide-cel) in Patients with Clinical High-Risk Newly Diagnosed Multiple Myeloma (NDMM) with an Inadequate Response to Frontline Autologous Stem Cell Transplantation (ASCT): KarMMa-2 Cohort 2c Extended Follow-up

Introduction Patients (pts) with multiple myeloma (MM) have a higher risk of progression/death following an inadequate response to frontline ASCT (van de Velde Eur J Haematol 2017). Therapies (Tx) with novel mechanisms of action may further improve response outcomes. Ide-cel previously demonstrated frequent, deep, and durable responses in KarMMa (Munshi N Engl J Med 2021) and significantly improved median progression-free survival (PFS) and overall response rate (ORR) versus standard regimens in KarMMa-3 (Rodríguez-Otero N Engl J Med 2023) in pts with triple-class-exposed relapsed and refractory MM. KarMMa-2 (NCT03601078) is a multicohort, phase 2, multicenter trial evaluating the efficacy and safety of ide-cel in pts with MM; cohort 2c included pts with NDMM who had an inadequate response to frontline Tx with ASCT. In cohort 2c, with a median follow-up of 27.9 months, ide-cel demonstrated deep and durable responses; complete response (CR) rate was 74.2% (ORR, 87.1%), with a 24-month PFS rate of 83.1% (Dhodapkar Blood 2022). Here, we report results with an additional 11.5 months of median follow-up for updated efficacy and safety data, and health-related quality of life (HRQoL) outcomes in cohort 2c. Methods Eligible pts had NDMM, received ≥ 3 cycles of induction Tx (including a proteasome inhibitor, an immunomodulatory agent, and dexamethasone), had < very good partial response (VGPR) 70-110 days after ASCT (single/tandem), and had Eastern Cooperative Oncology Group performance status ≤ 1. Pts received a single infusion of ide-cel (dose range: 150-450 × 10 6 CAR+ T cells) after lymphodepletion and could receive maintenance Tx post-infusion at investigator's discretion. The primary endpoint CR rate and secondary endpoints ORR, duration of response (DOR), PFS, overall survival (OS), safety, and patient-reported outcomes on HRQoL, assessed via European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) and EORTC Quality of Life Multiple Myeloma Module 20 Questionnaire (QLQ-MY20), are reported. The exploratory endpoint of minimal residual disease (MRD) negativity (sensitivity, 10 -5) is also reported. Results At data cutoff (May 3, 2023), with a median follow-up of 39.4 (range, 31.6-44.7) months, all 31 pts who were infused with ide-cel were alive; 28 (90.3%) remained in follow-up, with 3 (9.7%) having discontinued due to disease progression. The ORR and CR rates were 87.1% and 77.4%, respectively ( Table); best overall response in 1 pt improved from VGPR to stringent CR. The median DOR was not reached (NR; 95% CI, NR-NR), neither was median PFS (95% CI, 38.0-NR) or median OS (95% CI, NR-NR); the 36-month event-free rates were 80.9%, 76.8%, and 100.0%, respectively. In pts who did not receive lenalidomide (LEN) maintenance, 9 (29.0%) had disease progression; of the 8 pts who received LEN maintenance post ide-cel infusion, none experienced disease progression. At 36 months, MRD negativity was confirmed in 9/14 (64.3%) evaluable pts; all 9 achieved ≥ CR. In this extended follow-up, safety results were generally consistent with the previous data cutoff. All pts experienced ≥ 1 any-grade adverse event (AE), most commonly hematologic, including neutropenia (80.6%), anemia (38.7%), leukopenia (32.3%), and thrombocytopenia (29.0%); infection and infestation AEs occurred in 74.2% of pts. No grade 5 AEs were reported. Incidence of any-grade cytokine release syndrome (58.1%; no grade ≥ 3) was unchanged and there were no additional reports of parkinsonism since the previous report. Overall, HRQoL improved ( Figure) and MM disease symptoms were stable over time based on the EORTC QLQ-C30 and QLQ-MY20, respectively, following ide-cel treatment; by month 3, > 75% of pts had improved or stable global health status/QoL. Conclusions Ide-cel continued to demonstrate deep, durable responses in pts with an inadequate response to frontline ASCT, no new safety signals were observed with extended follow-up, and no deaths were reported. No pts who received LEN maintenance post ide-cel experienced disease progression. Ide-cel treatment resulted in stable or improved HRQoL. Overall, ide-cel continued to demonstrate a favorable clinical benefit-risk profile in NDMM after ASCT. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Outcomes of Patients Receiving Intensive Therapy for Acute Myeloid Leukemia Relapsed after/Refractory to Frontline Less-Intensive Therapy

Background: Hypomethylating agent (HMA) and venetoclax (Ven) frontline therapy for acute myeloid leukemia (AML) is astandard of care for patients (pts) deemed to be poor candidates for intensive induction due to age or fitness. However, given its attractive risk-benefit ratio, there is an increasing interest to extend the preference for HMA + Ven to other pts, including those who are fit for intensive therapy but with adverse risk disease. Unfortunately, most pts treated in this fashion will require future therapies for relapsed/refractory (R/R) disease and intensive therapy is given consideration mostly for pts with a path to allogeneic hematopoietic stem cell transplantation (alloHCT). Little is known about the outcomes of pts who receive intensive induction therapy after use of a frontline less-intensive regimen in the modern era. In this multi-center study, we seek to describe the experience with such a patient population and identify predictors of differential clinical outcomes. Methods: We conducted a multi-center, retrospective study of pts with AML treated with frontline less-intensive chemotherapy, followed by intensive induction chemotherapy for R/R disease. We first described the baseline characteristics of this cohort. Nominal variables were summarized with frequency and percentage while continuous variables were summarized with median and interquartile range (IQR). Overall response rate (ORR) was defined as complete remission (CR), complete remission with incomplete count recovery, or morphologic leukemia free state. Differences in ORR were analyzed with Fisher's exact test for nominal variables and Wilcoxon rank-sum test was used for continuous variables. Kaplan-Meier analysis was used to determine median overall survival (OS) after induction chemotherapy. Log-rank testing and Cox proportional hazard models were used to determine survival differences for nominal and continuous variables, respectively. Statistical significance was determined as p-value <0.05. Results: A total of 23 pts were included in this study. Median age at diagnosis was 64 years (IQR: 62-71). The majority of pts were male (n=12, 52%), white (n=20, 87%), and had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 (n=18, 82%). The majority of pts (61%) at time of frontline therapy had AML arising out of MDS. As expected, the majority of pts had adverse risk ELN cytogenetics (n=16, 70%) with an enrichment for disease harboring TP53 mutation (n=6, 27%) and complex karyotype (n=9, 39%). Fifteen pts (65%) had frontline therapy with azacitidine backbone, 6 pts (26%) with decitabine; some pts received both before intensive therapy. The median number of cycles of frontline therapy was 2 (IQR: 2-5). Median WBC at time of R/R therapy was 1.9 x 10 9/L (IQR: 0.8-6.45), while hemoglobin was 8.4 g/dL (IQR: 7.5-9.45), platelets were 41 x 10 9/L (IQR: 19.5-116.5), and marrow blasts were 25% (IQR: 16.5-30%). The plurality of pts received CPX-351 as intensive R/R therapy (n=9, 39%). Other regimens included 7+3 (n=2, 9%), FLAG-Ida + Ven (n=2, 9%), HiDAC + Mitoxantrone +/- Ven (n=4, 17%) ( Table 1). ORR after intensive R/R therapy was 27% (n=6), with 23% achieving CR. CPX-351 after HMA + Ven was specifically associated with an ORR of 33% (CR rate 22%). Median OS after initiation was 5.8 months. Thirty- and 60-day mortality was 17% and 26%, respectively. Five patients (23%) proceeded to alloHCT ( Table 1). Univariate differences in response rate and median survival were analyzed for each of the aforementioned variables as illustrated in Table 1. While none of the covariates reached statistical significance for impacting ORR or OS, ECOG PS trended towards significantly impacting OS ( p=0.074) and the median OS among patients proceeding to alloHCT was numerically doubled (8.0 vs. 4.0 months, p=0.11) ( Figure 1). Conclusions: Intensive therapy for R/R AML after prior frontline less-intensive therapy was associated with an ORR rate of 27% and median OS of 5.8 months in our cohort. This approach may be an appropriate strategy for a subset of pts, particularly those eligible for alloHCT. The relatively small and heterogeneous nature of this cohort limits strong conclusions regarding efficacy. As the use of frontline HMA + Ven continues to expand, further studies with larger sample size are needed to determine which pts would and would not benefit from intensive induction therapy in the R/R setting.

Ultra Low-Dose Radiation for Extranodal Marginal Zone Lymphoma of the Lung

Definitive radiation treatment (RT) for extranodal marginal zone lymphoma (ENMZL) of mucosal associated lymphoid tissue historically involves treatment to 24-30 Gy. There is increasing data supporting the use of ultra-low dose RT as part of a response-adapted approach in the treatment of orbital and gastric ENMZL. With this approach, patients receive initial treatment with 4 Gy, and additional RT is considered for those with persistent or locally progressive disease. However limited data to date assesses the efficacy of 4 Gy in the management of ENMZL of the lung. We performed an IRB-approved retrospective review of 17 patients with ENMZL of the lung treated with 4 Gy between 7/2015 and 12/2022 with response assessed after RT. Clinical/treatment characteristics, response, and toxicity were extracted from medical records. Statistics were performed using Mann-Whitney U and Fisher's Exact Test. Eight patients (47%) were female, 15 (88%) white, and 1 (6%) Hispanic. Median age at RT was 66 (interquartile range (IQR) 59-77). All had disease limited to the lung at diagnosis and 15 had stage IE disease. Four patients (24%) were diagnosed incidentally on screening/surveillance imaging in the absence of symptoms. Sixteen patients received 4 Gy in 2 fractions, while one patient received a single fraction of 4 Gy. Median SUVmax prior to RT was 4.5 (IQR 3.2-7.2). Median planning target volume (PTV) was 74 cc (IQR 47-130cc). Six patients (35%) had respiratory symptoms prior to RT, which improved or resolved in 3 (50%). A larger PTV was associated with improvement in symptoms following RT with a median PTV of 266 cc (IQR 171-402) in those who experienced improvement vs. 64 cc (IQR 42-100) in those who did not (p = 0.032). One patient experienced toxicity following RT with pleuritic chest pain, which resolved with corticosteroids. At a median follow-up of 15 months following RT (IQR 7-43 months), the overall response rate (ORR) was 100% (CR, n = 15; PR, n = 2). Fourteen patients had follow-up PET/CT, of whom 13 had a complete metabolic response (CMR) at a median of 3 months following RT (IQR 3-5 months). Two additional patients had a complete response (CR) on CT while one had a partial response on CT. Achieving a CR was not associated with SUV prior to RT (p = 0.50) or PTV size (p = 0.62). In patients with stage IE disease, the ORR rate was 100% and there have been no distant failures to date. Fifteen of 17 patients were alive at last follow-up; two passed away of unrelated causes (one from Alzheimer's disease and one from recurrent squamous cell carcinoma). Ultra-low dose radiation of 4 Gy is associated with excellent local control in the management of ENMZL of the lung and is very well tolerated. Four Gy was effective for local control and symptom palliation even for larger tumors and is an effective initial therapy as part of a response-adapted approach even in limited stage patients.

The Role of Radiotherapy in Patients with Refractory Hodgkin Lymphoma after Brentuximab Vedotin and -/or Immune Checkpoint Inhibitors

Brentuximab vedotin (BV) and immune checkpoint inhibitors (ICIs) had important roles in the treatment of relapse or refractory (R/R) Hodgkin lymphoma (HL). Treatment of refractory disease after BV and -/or ICIs remains a challenge. This study was conducted to evaluate the efficacy and safety of radiotherapy for R/R HL after failure to BV or ICIs. We retrospectively analyzed patients in two institutions with R/R HL who had failed after first-line therapy, and were refractory to BV or ICIs, and received radiotherapy (RT) thereafter. The overall response rate (ORR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were analyzed. A total of 19 patients were enrolled. First-line systemic therapy consisted of ABVD (84.2%), AVD + ICIs (10.5%) and BEACOPP (5.3%), respectively. After first-line therapy, 15 patients (78.9%) were refractory, and 4 patients (21.1%) relapsed. After diagnosis of R/R HL, 8 patients (42.1%) received BV, and 17 patients (89.5%) received ICIs. RT was delivered in all 19 patients who failed after BV or ICIs. In 16 efficacy-evaluable patients, the ORR and CR rate were 100% and 100%. The median DOR was 17.2 months (range, 7.9 to 46.7 months). 3 patients progressed at outside of the radiation field. The in-field-response rate was 100%. The 12-month PFS and OS were 84.4% and 100%, respectively. No patients were reported with sever adverse events. This study concluded that radiotherapy was effective and safe for refractory HL after BV or ICIs. Further prospective studies were warranted.

Efficacy of Bendamustine, Pomalidomide, and Dexamethasone (BPD) Regimen in Relapsed/Refractory Extramedullary Myeloma: A Retrospective Single-Centre Study, Real-Life Experience.

Relapsed/refractory extramedullary myeloma (RREMM) is an uncommon and aggressive subtype of multiple myeloma defined by plasma cell proliferation outside the bone marrow. Therapeutic options for RREMM are limited, and the prognosis is generally unfavorable. This research aimed to assess the effectiveness of the bendamustine, pomalidomide, and dexamethasone (BPD) regimen in patients with RREMM. We carried out a retrospective investigation of 11 RREMM patients who underwent BPD treatment. The primary endpoint was progression-free survival. The secondary endpoints of the study were two-year survival and overall response rate (ORR). We analyzed the sociodemographic and clinical features of the patients. The average age of the patients was 62 years. They had a median of four prior treatment lines, and eight patients had previously received autologous stem-cell transplantation. After eight BPD treatment cycles, the ORR stood at 54%, with one very good partial response (VGPR), five partial responses (PR), three progressive diseases (PD), and two stable diseases (SD). The median follow-up was 15 months, with a two-year PFS rate of 71.3% and a two-year survival rate of 81.8%. The BPD regimen demonstrated promising effectiveness in RREMM patients, yielding favorable ORR and survival rates. To corroborate these findings and explore additional treatment alternatives for this patient group, larger prospective studies are required.

Combination of venetoclax with BCR-ABL tyrosine kinase inhibitor as a therapeutic strategy for Philadelphia chromosome-positive leukemias

ABSTRACTObjectives:Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKIs) in preclinical studies for patients with Philadelphia chromosome-positive (Ph+) leukemias. This combination may suggest a novel treatment strategy for Ph + leukemias.Methods:We conducted a retrospective study to summarize the activity of combining venetoclax and BCR-ABL1 TKI-based therapies in Ph + leukemias.Result:A total of 18 patients with Ph + leukemias were enrolled in this study. At the time of venetoclax and TKI-based therapy, 5 patients were initially diagnosed, with Ph + acute myeloid leukemia (AML) (n = 1) and mixed phenotype acute leukemia (MPAL) (n = 4), 7 patients had chronic myeloid leukemia at blastic phase (CML-BP), and the remaining 6 patients had relapsed or refractory to prior therapy. The overall response rate (ORR) was 88.9% (9 CR, 2 CRi, 4 MLFS, 1 PR), and a major molecular response (MMR) (or better) was achieved in 7 (38.8%) of all patients. With a median follow-up of 7.0 months (range, 2.3-15.6), 15 (83.3%) were in continuous CR at the time of this analysis, with a 1-year OS of 85.6%, 1-year LFS of 76.7%, and 1-year CIR of 22.4%. Moreover, 10 of 18 patients were treated with venetoclax, TKI and hypomethylating agent (HMA) regimens, which also associated with a high ORR rate (6 CR, 1 CRi, 3 MLFS), and can be used for induction or salvage therapy.Conclusion:Venetoclax and TKI-based combination regimens may be a feasible approach for Ph + leukemias, and prospective studies are needed to properly assess the safety, tolerability and efficacy of this regimen.

Assessing the efficacy of palliative radiation treatment schemes for locally advanced squamous cell carcinoma of the head and neck: a meta-analysis.

The objective to assess the outcomes from different palliative radiotherapy (RT) schedules in incurable head and neck cancer (HNC), to evaluate if there is a relationship between RT dose, technique, and fractionation with tumor response in contrast to the occurrence of adverse effects. Eligible studies were identified on Medline, Embase, the Cochrane Library, and annual meetings proceedings through June 2020. Following PRISMA and MOOSE guidelines, a cumulative meta-analysis of studies for overall response rate (ORR), overall survival (OS), progression-free survival (PFS), pain/dysphagia relief, and toxicity was performed. A meta-regression analysis was done to assess if there is a connection between RT dose, schedule, and technique with ORR. Twenty-eight studies with 1,986 patients treated with palliative RT due to incurable HNC were included. The median OS was 6.5 months [95% confidence interval (CI): 5.6-7.4], and PFS was 3.6 months (95% CI: 2.7-4.3). The ORR, pain and dysphagia relief rates were 72% (95% CI: 0.6-0.8), 83% (95% CI: 52-100%), and 75% (95% CI: 52-100%), respectively. Conventional radiotherapy (2D-RT) or conformational radiotherapy (3D-RT) use were significantly associated with a higher acute toxicity rate (grade ≥ 3) than intensity-modulated radiation therapy (IMRT) or stereotactic body radiation therapy (SBRT). On meta-regression analyses, the total biological effective doses (BED) of RT (p = 0.001), BED > 60 Gy10 (p = 0.001), short course (p = 0.01) and SBRT (p = 0.02) were associated with a superior ORR. Palliative RT achieves tumor response and symptom relief in incurable HNC patients. Short course RT of BED > 60 Gy using IMRT could improve its therapeutic ratio. SBRT should be considered when available.

Pembrolizumab plus vorinostat induces responses in patients with Hodgkin lymphoma refractory to prior PD-1 blockade

AbstractThis phase 1 study evaluated the addition of vorinostat to pembrolizumab in patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma, and follicular lymphoma. We report the results in cases of cHL. Adult patients with RR cHL who had received ≥1 prior lines of therapy and were ineligible for transplantation were treated in a dose-escalation cohort with 2 dose levels (DLs) and then on an expansion cohort at the recommended phase 2 dose (RP2D) in 21-day cycles. Vorinostat 100 mg twice a day (DL1) and 200 mg twice a day (DL2) was administered orally from days 1 to 5 and 8 to 12; all patients received pembrolizumab 200 mg IV every 3 weeks. The primary end point was safety and determination of RP2D. In total, 32 patients with cHL were enrolled, including 30 at DL2 (RP2D); 78% had received prior anti–programmed cell death 1 (anti–PD-1) therapy, and 56% were PD-1 refractory. Grade ≥3 adverse events (AEs) included hypertension (9%), neutropenia (9%), hypophosphatemia (9%), thrombocytopenia (6%), and lymphopenia (6%). Immune-related AEs included grade 1 or 2 thyroiditis (13%), grade 1 rash (6%), and grade 3 esophagitis/duodenitis (3%). The overall response rate (ORR) was 72% and complete response (CR) rate was 34%. Patients refractory to prior PD-1 blockade (n = 18) had ORR and CR rates of 56% and 11%, respectively. Pembrolizumab and vorinostat was well tolerated with a high ORR rate in RR cHL including in anti–PD-1–refractory disease. This trial was registered at www.clinicaltrials.gov as #NCT03150329.

Second-line therapy for patients with steroid-refractory aGVHD: systematic review and meta-analysis of randomized controlled trials.

Steroids-refractory (SR) acute graft-versus-host disease (aGVHD) is a life-threatening condition in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the optimal second-line therapy still has not been established. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of different second-line therapy regimens. Literature search in MEDLINE, Embase, Cochrane Library and China Biology Medicine databases were performed to retrieve RCTs comparing the efficacy and safety of different therapy regimens for patients with SR aGVHD. Meta-analysis was conducted with Review Manager version 5.3. The primary outcome is the overall response rate (ORR) at day 28. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated with the Mantel-Haenszel method. Eight eligible RCTs were included, involving 1127 patients with SR aGVHD and a broad range of second-line therapy regimens. Meta-analysis of 3 trials investigating the effects of adding mesenchymal stroma cells (MSCs) to other second-line therapy regimens suggested that the addition of MSCs is associated with significantly improvement in ORR at day 28 (RR = 1.15, 95% CI = 1.01-1.32, P = 0.04), especially in patients with severe (grade III-IV or grade C-D) aGVHD (RR = 1.26, 95% CI = 1.04-1.52, P = 0.02) and patients with multiorgan involved (RR = 1.27, 95% CI = 1.05-1.55, P = 0.01). No significant difference was observed betwwen the MSCs group and control group in consideration of overall survival and serious adverse events. Treatment outcomes of the other trials were comprehensively reviewed, ruxolitinib showed significantly higher ORR and complete response rate at day 28, higher durable overall response at day 56 and longer failure-free survival in comparison with other regimens; inolimomab shows similar 1-year therapy success rate but superior long-term overall survial in comparison with anti-thymocyte globulin, other comparisons did not show significant differences in efficacy. Adding MSCs to other second-line therapy regimens is associated with significantly improved ORR, ruxolitinib showed significantly better efficacy outcomes in comparison with other regimens in patients with SR aGVHD. Further well-designed RCTs and integrated studies are required to determine the optimal treatment. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022342487.

TREATMENT PATTERNS IN PATIENTS WITH MANTLE CELL LYMPHOMA: UPDATED REPORT OF THE ASIA‐PACIFIC MULTINATIONAL RETROSPECTIVE REGISTRY STUDY

Introduction: We conducted a multinational, multicenter retrospective registry study to better define the treatment patterns and survival outcomes of newly diagnosed patients with mantle cell lymphoma (MCL) in the Asia-Pacific region. Methods: Data were collected from newly diagnosed MCL patients between January 2008 and September 2019 from 27 hospitals in Asian countries, including China, Malaysia, Japan, Singapore, South Korea, Taiwan, and Thailand. The first interim analysis with 191 patients was previously reported. An updated analysis of 289 patients was performed at the data cutoff date of December 19, 2022. Results: The median age was 64 years (range, 26–90), and 213 patients were male (73.7%). The majority of the patients had stage 3 or 4 diseases (n = 249, 86.2%). The most frequently administered 1st line regimen was R-CHOP or R-CHOP-like regimens (n = 146), followed by cytarabine-containing regimens (n = 78) including R-Hyper-CVAD (n = 56), and bendamustine-rituximab (n = 22) (Figure 1A). Higher proportion of elderly patients received R-CHOP or R-CHOP-like regimens, while cytarabine-containing regimens were more frequently administered in young patients (Figure 1B). The overall response rate (ORR) and the complete response (CR) rate among these patients were 94.7% and 59.0%, respectively. The ORR and CR rates for each regimen were as follows; R-CHOP or R-CHOP-like regimens (ORR 97.0%, CR 52.2%), cytarabine-containing regimens (ORR 94.6%, CR 65.3%), and bendamustine-rituximab (ORR 95.2%, CR 76.2%). Median progression-free survival (PFS) was 47.6 months, and median overall survival (OS) was 75.7 months. The median PFS was 41.1 months for R-CHOP or R-CHOP-like regimens, 60.8 months for cytarabine-containing regimens, and 71.0 months for bendamustine-rituximab. Twenty-nine patients received rituximab maintenance treatment, and the survival outcomes regarding maintenance therapy will be updated and presented at the ICML 2023. There were no significant differences in PFS and OS between the ASCT (n = 103) and non-ASCT (n = 35) groups among transplant-eligible patients (n=138), with a 5-year PFS rate of 48.6 versus 32.5% (P = 0.29) and 5-year OS rate of 73.7 versus 73.7% (P= 0.13), respectively. A total of 152 patients were given the 2nd line regimens. The most commonly used regimen was ibrutinib (n = 45), followed by cytarabine-based regimens (n = 38). The median 2nd PFS was 17.3 months. Keyword: Aggressive B-cell non-Hodgkin lymphoma The research was funded by: The work was funded by a research grant from Janssen Pharmaceuticals Ltd. No conflicts of interests pertinent to the abstract.

Response-adapted therapy (tx) with nivolumab plus brentuximab vedotin (nivo + BV) without autologous hematopoietic cell transplantation (auto-HCT) in children, adolescents, and young adults (CAYA) with low-risk relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL): CheckMate 744.

7515 Background: Outcomes are poor for patients (pts) with cHL who develop R/R disease after first-line (1L) chemotherapy ± radiotherapy (RT). Salvage tx that attain high event-free survival (EFS) rates and minimize late toxicity by omitting high-dose chemotherapy (HDCT)/auto-HCT are needed. CheckMate 744 (NCT02927769) is the first multicenter phase 2 study evaluating a risk-stratified, response-adapted salvage tx with nivo + BV in CAYA with R/R cHL. In the standard-risk cohort, complete molecular response (CMR) rate before consolidation with HDCT/auto-HCT was 94% (Harker-Murray et al. Blood 2022). With highly active salvage tx, pts in low-risk cohort could achieve high EFS without HDCT/auto-HCT; we report data from this cohort. Methods: Pts were aged 5–30 y and had ≤ 3 cycles (C) of 1L anthracycline-based systemic tx. Risk stratification was described in Harker-Murray et al. Pts received 4C of nivo + BV induction. Pts with CMR received additional 2C nivo + BV before involved-site radiation therapy (ISRT) consolidation (dose, 30–30.6 Gy). Pts with suboptimal response received 2C BV + bendamustine intensification; pts with CMR proceeded to ISRT consolidation. Primary endpoints: CMR rate (Lugano 2014) any time before ISRT and 3-y EFS rate, both per blinded independent central review (BICR). For CMR and overall response rate (ORR), a 90% confidence interval (CI) was used per statistical plan. Results: Among 28 pts treated with nivo + BV, median (range) age was 17 (6–27) y; 64% of pts were aged < 18 y. Most (64%) pts had stage II disease at relapse; 82% had relapse ≥ 12 mo after 1L tx, 2 pts had prior RT. Median (range) follow-up was 31.9 (2.2–55.3) mo. CMR, ORR, 3-y EFS and PFS rates are shown in Table. Median duration of response was not reached; 87% of pts had sustained response at 36 mo’ follow-up. Efficacy outcomes were comparable in the pediatric population (CMR per BICR before ISRT, 88.9%; 3-y EFS rate, 78.3%). During induction, 22 (78.6%) pts had treatment-related adverse events (TRAEs; grade 3/4, 25.0% pts; hematologic, < 10% pts; immune-mediated, 21.4%). Serious AEs leading to discontinuation included rash, pyrexia, and acute kidney injury (1 pt each). Conclusions: The findings demonstrate that most CAYA with low-risk R/R cHL can be salvaged with chemoimmunotherapy with a favorable toxicity profile, and do not require HDCT/auto-HCT. Clinical trial information: NCT02927769 . [Table: see text]

FLOT plus nivolumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: Results from the randomized phase 2 IKF-S628/AIO-STO-0417 (Moonlight) trial of the AIO.

4045 Background: FOLFOX plus nivolumab (nivo) has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas. FLOT is a well-established standard of care triplet regime. Some physicians may consider a triplet in patients with aggressive disease. The aim of this Arm C part of the Moonlight trial was to evaluate the safety and efficacy of the combination of FLOT plus nivo. Methods: Moonlight is a multi-cohort phase-II trial. The results for Arm C evaluating FLOT + nivo (240 mg) q2w as first-line therapy in all-comers are presented here. Primary endpoint was progression-free survival at 6 months (PFS@6), main secondary endpoints were safety, OS, and overall response rate (ORR). Results: Fifty-two patients were enrolled. Baseline characteristics were: median age 61y, GEJ 65%. Sixty-five percent had centrally assessed PD-L1 CPS≥1 (available in 96% of pts). Pts. received a median number of 8 cycles of FLOT and nivo and 42% received further line treatment. FLOT plus nivo was well tolerated and feasible with the most frequent adverse events of ≥ grade 3 being decreased neutrophils (40.4%), anemia (5.8%) and thromboembolic events (7.7%). After a median follow-up of 9.4 months, 3- and 6-month progression-free survival rates were 85% and 42%, respectively. Median PFS was 6.6 months and median OS 10.8 months. ORR and disease control rate (DCR) were 54% and 87%, respectively. Compared to the pooled study cohorts A and A1 (n = 90 pts) utilizing mFOLFOX plus nivo and ipilimumab (non-randomized comparison), FLOT plus nivo was associated with greater DCR (87% vs. 78%) and 3-months PFS (85% vs. 72%). Conclusions: FLOT and nivo is feasible and seems to be associated with improved disease control in the early course of therapy. FLOT plus nivo may represent an option for select patients with aggressive, rapidly progressive disease. Clinical trial information: NCT03647969 .

Effectiveness and safety of encorafenib-cetuximab in BRAFV600E metastatic colorectal cancer: Confidence study.

126 Background: BRAFV600E mutant metastatic colorectal cancer (mCRC) has a poor prognosis. The BEACON trial demonstrated an improvement in tumor response, overall survival (OS), and progression-free survival (PFS) when administering encorafenib-cetuximab (EC) to patients (pts) who progressed after 1 or 2 therapy lines. This study provides a retrospective analysis of the effectiveness and safety of EC in the real-world setting in Spain. Methods: This retrospective analysis included BRAFV600E mCRC pts treated with EC in 2nd line treatment, recruited from March to July 2022. The Co-primary study endpoints included effectiveness based on PFS and OS. Secondary endpoints included sociodemographic and clinical characteristics of patients before EC initiation, overall response rate (ORR), and safety. Results: From March to July 2022, 81 evaluable pts were included. Sociodemographic and clinical characteristics are displayed.A median (interquartile range [IQR]) of 6.0 (4.0-13.0) cycles of encorafenib and 6.0 (4.0-14.5) cycles of cetuximab were administered. Median treatment duration was 4.4 (2.6-7.8) months (m) and 4.4 m (2.8-7.6) respectively. The ORR and disease control rate was 33.8 % (CI 95% 23.4-45.5) and 68.8 (CI 95% 57.3 – 78.9) respectively. One (1.2%) pt achieved complete response At data cut-offwith a 9.7 median follow-up, 50 (61.7%) pts had died, all of them due to disease progression. Median (95% Confidence Interval, CI) OS was 12.6 m (8.0-17.3) and median PFS was 5.0 m (3.8-6.2). The 12-m OS and 12-m PFS rates were 54.6% (95% CI, 43.3-65.9) and 19.9% (10.5-29.3) respectively. Pts with neutrophils/lymphocyte ratio (NLR) ≥3 had worse OS (HR, 1.8 95% CI 1.0-3.2; p < 0.049) and worse PFS (HR, 2.3, 1.4-3.8; p < 0.002). Disease progression (86.7%) was the most frequent cause of treatment discontinuation, followed by unacceptable AEs (3.7%). Eleven pts (13.5%) experienced treatment-related graded 3 or 4 AEs, mainly acne (3.7%). Treatment-related deaths were not reported. Conclusions: This study provides real-world data of BRAFV600E mCRC pts treated with EC combination in routine clinical practice in Spain. EC effectiveness and safety were consistent with the results obtained in clinical trials. [Table: see text]

Efficacy and safety of cyclosporine-based regimens for primary immune thrombocytopenia: a systematic review and meta-analysis.

To conduct a meta-analysis assessing the efficacy and safety of cyclosporine-based combinations for primary immune thrombocytopenia (ITP). Randomized controlled clinical trials were collected by systematically searching databases (PubMed®, MEDLINE®, EMBASE, The Cochrane Library, China National Knowledge Infrastructure) from inception to June 2022. All studies included patients with ITP who received cyclosporine-based regimens. We performed comprehensive analyses of the overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, relapse rate, platelet count, and adverse drug reaction (ADR) rate. Seven studies (n = 418) were ultimately included. According to a fixed-effects model, cyclosporine-based combinations improved the ORR and CR rate and reduced the relapse rate. The ADR rate was not increased in the cyclosporine-based combination group. Cyclosporine-based regimens effectively increased the platelet count. Subgroup analysis illustrated that cyclosporine-based combinations were linked to higher ORRs in both children (odds ratio [OR] = 5.74, 95% confidence interval [CI] = 1.79-18.41) and adults (OR = 5.46, 95% CI = 2.48-12.02) and a higher CR rate in adults (OR = 2.97, 95% CI = 1.56-5.63). Cyclosporine exhibited efficacy in the treatment of ITP without increasing the risk of ADRs.

Objective response rate of placebo in randomized controlled trials of anticancer medicines.

Spontaneous regression of advanced solid tumors is infrequent but may occur. Quantifying response rates from placebo in cancer drug trials may provide important information for physicians, patients, and regulators. We aimed to provide a pooled placebo response rate from drug trials in advanced solid tumors. We pooled the overall response rate (ORR), complete response rate (CR) and partial response rates (PR) in the placebo arm of placebo-controlled randomized controlled trials (RCTs) of cancer drugs for advanced solid tumors published during 2015-2021 using random-effects model. 45 phase 3 RCTs including 5684 patients on placebo met our inclusion criteria and formed the study cohort. The pooled overall ORR, CR and PR rates in the placebo arm were 1% (95% CI, 0%-2%), 0% (95% CI, 0%-0%), and 1% (95% CI, 0%-2%) respectively. Higher placebo responses were observed in prostate cancer and sarcoma trials. Overall, 1% patients with advanced solid tumors can expect to achieve some response even in absence of treatment. However, complete regression without treatment is extremely rare, almost zero percent. This information will be helpful to patients in their decisions, as well as regulators in evaluating cancer drugs' efficacy based on response rates alone. None.

Updated Phase IIb Results of Venetoclax with FLAG-IDA in Relapsed or Refractory Acute Myeloid Leukemia

Background: Patients(pts) with relapsed or refractory (R/R) AML experience poor response rates and short durations of response. FLAG-IDA salvage therapy has previously demonstrated a composite remission rate (CRc) of 21% with median OS (mOS) of 3.5 months (Roboz, JCO 2014). Combinations of BCL2 inhibition have proven to be synergistic with low intensity and intensive chemotherapy, with improved CRc and mOS rates. Venetoclax with FLAG-IDA demonstrated favorable response rates in the frontline and relapsed or refractory (R/R) setting, with overall response rate (ORR) of 97% and 70% in the Phase IIA (frontline) and Phase IIB (R/R) respectively (JCO 2021). Here we present updated results of the Phase IIb cohort. Methods: Pts >18 years of age with R/R AML, defined as lack of response after at least 1 cycle of induction or relapsed disease with any prior number of treatments but without prior receipt of venetoclax, with sustained organ function were eligible. Induction consisted of fludarabine (30mg/m2, D2-6), cytarabine (1.5g/m2 D2-6), idarubicin (6mg/m2, D4-5), and Filgrastim(D1-7). Venetoclax was administered D1-14 during induction and D1-7 for consolidation (100mg D1, 200mg D2, 400mg onwards for induction). Consolidation consisted of fludarabine(30mg/m2) and cytarabine (1.5g/m2) for D2-4. The primary objective was evaluation of ORR. Secondary objectives included overall survival (OS), CRc, and duration of response (DOR). Mutation analysis was performed using next-generation sequencing and measurable residual disease (MRD) detection was performed using flow cytometry (sensitivity 10-3-10-4). Results: Thirty-three R/R pts have been treated. Baseline characteristics are shown in Table 1. The median age was 47 (range 18 to 68). For 70% of pts, this regimen was Salvage 1. Thirty percent of pts underwent prior SCT. The majority of pts had ELN 2017 adverse risk disease (67%).Complex karyotype and TP53 mutations occurred in 19% and 21% of pts respectively. Among the 33 pts, 1 patient remains too early for response assessment. The ORR of the remaining 32 pts was 60% (19 pts), with CRc rate of 53% and 12 pts (71% of responders) achieving MRD negativity. ORR and CRc rates in salvage 1 pt were 65% and 61%. By ELN risk, ORR and CRc rates were 100% and 85% in favorable risk, 50%and 50% in intermediate risk, and 48% and 43% in adverse risk. ORR and CRc rates for TP53 wild-type vs TP53 mutant was 68% and 14%, vs 64% and 14%. The median number of cycles received was 2 (range 1-4) with a median number of cycles to best response of 1 (range 1-2). Among responding pts, 13 (68%) proceeded to allogeneic transplant, including two pts who transitioned to HMA + VEN and sorafenib maintenance, respectively prior to transplant. At a median follow up of 15.8 months, the OS and DOR were 27 (95% CI 22.3-26.3) months and NR (95% CI 22.4-NR) respectively. Six-month and 12-month survival was 69% and 60%, respectively. Of the 13 pts that proceeding with transplant, median DOR post-transplant has not been reached. OS in TP53 wild-type vs TP53 mutant was NR and 5.4 months with a 12-month OS of 68% and 17% respectively. Thirty-day and 60 day- mortality was 0% and 12%. Two deaths occurred within 60 days in pts with persistent leukemia (secondary to hemoptysis from known fungal pneumonia and disease). Conclusion: In a cohort of pts with R/R AML enriched for fit pts with adverse-risk disease, this intensive combination resulted in an ORR of 60% with a CRc of 53%. Seventy-one percent of CRc pts attained an MRD negative remission and 68% of responding pts proceeded to transplant. In conclusion, this regimen is associated with deep remissions and a high rate of transition to transplant inpatients with R/R AML, particularly in TP53 wild-type. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Indirect Comparisons of the Efficacy of Subcutaneous Epcoritamab Vs Chemoimmunotherapy in Patients with Relapsed or Refractory Large B-Cell Lymphoma

Background: Epcoritamab is a novel, subcutaneous (SC) CD3xCD20 bispecific antibody that has been shown to be efficacious in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL) as monotherapy. The phase 1/2 EPCORE NHL-1 (NCT03625037) study evaluated epcoritamab in patients with R/R LBCL who received at least 2 prior lines of systemic therapy. Patients in the trial were heavily pretreated with a median of 3 (range, 2-11) prior lines of therapy, 39% had prior chimeric antigen receptor T-cell (CAR T) therapy, 61% had primary refractory disease, and 83% were refractory to the last line of therapy. With a median follow-up of 10.7 months, the overall response rate (ORR) by independent review committee based on Lugano criteria was 63%, with a complete response (CR) rate of 39%; median overall survival (OS) was not reached (Thieblemont et al, EHA 2022). No head-to-head data have compared SC epcoritamab with chemoimmunotherapy (CIT). This study conducted an unanchored, matching-adjusted, indirect comparison of the efficacy of SC epcoritamab as reported in the EPCORE NHL-1 trial with that of CIT as reported in the SCHOLAR-1 study (Neelapu et al, Blood Adv 2021), which is the largest reported outcomes study in patients with R/R LBLCL treated with CIT. Methods: Published OS data for CIT from SCHOLAR-1 and ORR and CR rate based on investigator-assessed International Working Group criteria were used to conduct this matching-adjusted, indirect treatment comparison versus epcoritamab. Patients with prior exposure to CAR T therapy enrolled in EPCORE NHL-1 were excluded in this analysis because the SCHOLAR-1 study only included patients without prior exposure to CAR T therapy. Analysis was conducted by adjusting for imbalances in the following baseline characteristics between individual patient-level data from EPCORE NHL-1 and aggregate data from SCHOLAR-1: age 65 years or older, sex, primary refractory disease, disease refractory to at least 2 consecutive lines of therapy, Eastern Cooperative Oncology Group performance status, relapse within 12 months of autologous stem cell transplant, and disease stages III and IV. Propensity score weights resulting from the adjustment were applied to estimate differences in risk for ORR and CR rate for epcoritamab versus CIT, and weighted Cox proportional hazards models were used to estimate the OS HR between the 2 comparators. Adjustment weights were truncated at 1% and 99% of their distribution to reduce occurrence of extreme weights. Results: Patients without prior exposure to CAR T therapy enrolled in the EPCORE NHL-1 trial (N = 96) were mostly 65 years and older, men, had stage III or IV disease, had a history of primary refractory disease, and were refractory to at least 2 consecutive lines of therapy (Table 1). After adjustment, imbalances of these baseline characteristic variables between EPCORE NHL-1 and SCHOLAR-1 were mitigated (Table 1). Before adjustment, the ORR, CR rate, and OS HRs for epcoritamab were 68.8%, 41.7%, and 0.443 (vs CIT), respectively, for patients naive to CAR T therapy (Table 2). After adjustment, compared with CIT, patients receiving epcoritamab had a higher adjusted ORR (74.5% vs 34.1%; difference in risk, 40.4%; P < 0.001) and CR rate (52.4% vs 12.1%; difference in risk, 40.4%; P < 0.001). After adjustment, patients treated with epcoritamab also had improved OS versus CIT (HR 0.283, 95% CI: 0.161-0.497; P < 0.001). The median OS for CIT was 5.4 months, whereas the median OS of epcoritamab had not yet been reached with a median follow-up of 10.7 months. Limitations: Although this study adjusts for confounding variables between trials, outcomes are still subject to a higher level of uncertainty than what would have occurred if epcoritamab and comparators were studied within a randomized controlled trial. In addition, adjustments are based on the aggregate proportions of patient characteristics so that the associations between survival and baseline factors on the study level may be different than they would have been on the patient level. Conclusions: Findings from this cross-study analysis suggest that epcoritamab demonstrated significantly better efficacy in a highly refractory LBCL population versus CIT. Despite lack of an available head-to-head comparison, this study contextualizes the epcoritamab data and underscores the therapeutic potential of epcoritamab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Glofitamab Monotherapy Induces High Complete Response Rates in Patients with Heavily Pretreated Relapsed or Refractory Mantle Cell Lymphoma

Background: New treatment options are needed for patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL), especially those with progressive disease (PD) after Bruton's tyrosine kinase inhibitor (BTKi) therapy. In a retrospective cohort study of 114 patients with MCL who had PD while receiving ibrutinib, median OS upon ending ibrutinib treatment was 2.9 months (95% CI: 1.6-4.9; Martin et al. Blood 2016). The CD20xCD3 T-cell-engaging bispecific monoclonal antibody, glofitamab, has a novel 2:1 (CD20:CD3) configuration with bivalency for CD20 on B cells and monovalency for CD3 on T cells. Obinutuzumab pretreatment (Gpt) is given 7 days prior to the first dose of glofitamab to mitigate the risk of cytokine release syndrome (CRS). Phase I/II (NCT03075696) data for glofitamab monotherapy with step-up dosing (SUD) and Gpt (1000mg or 2000mg) have shown high response rates and manageable, mostly low-grade CRS in patients with R/R MCL, most of whom had prior BTKi therapy (Phillips et al. ASH 2021). Here, we report on the durability of response with glofitamab SUD in a larger cohort with additional follow up. Methods: All patients received Gpt 7 days before the first dose of glofitamab. Intravenous glofitamab SUD was given on Days (D) 8 (2.5mg) and 15 (10mg) of Cycle (C) 1, then at the target dose (16mg or 30mg after 1000mg Gpt; 30mg after 2000mg Gpt) from C2D1, every 3 weeks for up to 12 cycles. Response rates were assessed by Lugano criteria (Cheson et al. JCO 2014). Results: As of March 14, 2022, 37 patients had received glofitamab SUD after Gpt (1000mg Gpt, n=16; 2000mg Gpt, n=21). Median age was 72.0 years (range: 41-84), 73.0% of patients were male, 91.9% had Ann Arbor Stage III/IV disease and 32.4% had MCL IPI score ≥6 at study entry. Median prior lines of therapy was three (range: 1-5); 24 (64.9%) patients had prior BTKi therapy and seven (18.9%) had prior lenalidomide therapy. The majority of patients were refractory to their first line of therapy (62.2%; n=23) and/or their last prior therapy (73.0%; n=27). Median time since last therapy was 1.9 months (range: 0.1-107.5). After a median follow up of 8 months (range: 0-19), overall response rate (ORR) and complete response (CR) rates were 83.8% (31/37) and 73.0% (27/37), respectively, across both Gpt cohorts. In the 2000mg Gpt cohort, ORR and CR rates were 90.5% (19/21) and 81.0% (17/21), respectively. In the 1000mg Gpt cohort, ORR and CR rates were 75.0% (12/16) and 62.5% (10/16), respectively. Across both Gpt cohorts, median time to CR was 51 days. The majority of CRs (20/27; 74.1%) were ongoing at the data cut-off and an estimated 71.6% of patients with a CR remained in response at 9 months. Median duration of response was 12.6 months (95% CI: 10.0-NE) and median duration of CR was 10.0 months (95% CI: 4.9-NE). The two deaths that occurred after 10 months were due to COVID-19 (Figure). In safety-evaluable patients (n=37), the most common adverse events (AEs) were CRS (75.7%; by ASTCT criteria) and neutropenia (40.5%). CRS rates were lower in the 2000mg Gpt (14/21; 66.7%) vs the 1000mg Gpt (14/16; 87.5%) cohort. CRS events in the 2000mg Gpt cohort were all Grade (Gr) 1-3 (Gr 1, 33.3%; Gr 2, 23.8%; Gr 3, 9.5%), whereas there were two Gr 4 CRS events in the 1000mg Gpt cohort (Gr 1, 25.0%; Gr 2, 37.5%; Gr 3, 12.5%; Gr 4, 12.5%). All CRS events were manageable (17 patients received tocilizumab to manage CRS) and most resolved by data cut-off (one patient had ongoing CRS at the time of analysis). Neurologic AEs (NAEs) occurred in 19 patients (51.4%); all were Gr 1/2 except for one Gr 3 subdural hematoma in the 2000mg Gpt cohort. NAEs consistent with immune effector cell-associated neurotoxicity syndrome following glofitamab administration occurred in five patients (13.5%, all Gr 1/2 and nonserious). Tumor flare events occurred in five patients (13.5%, all Gr 1/2). No patients discontinued treatment due to AEs. Ten deaths were reported and considered unrelated to study treatment: PD, n=5; AEs, n=5 (COVID-19/pneumonia, n=4; cardiac arrest, n=1). Conclusions: Fixed-duration glofitamab monotherapy after Gpt (1000mg or 2000mg) induced high and durable CR rates, the majority of which were achieved early, in heavily pretreated patients with MCL, most of whom had prior BTKi therapy and thus a particularly poor prognosis. CRS events were manageable and mostly low grade. This is one of the largest datasets and longest follow-ups reported with a CD20xCD3 bispecific monoclonal antibody for patients with R/R MCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal