Complete Metabolic Response Rate Research Articles

Impact of definitive radiotherapy on metabolic response measured with 68Ga-PSMA-PET/CT in patients with intermediate-risk prostate cancer.

To assess the early metabolic response of the primary tumor using Gallium-68 (68Ga)-labeled-prostate-specific membrane antigen positron emission tomography (68Ga-PSMA-PET/CT), as well as the relationship between PSMA change in the primary tumor and PSA response after definitive radiotherapy (RT), either alone or in combination with androgen deprivation therapy (ADT) in intermediate risk prostate cancer (IR-PCa) patients. The clinical data of 71 IR-PCa patients treated with RT alone (36 patients, 50.7%) or RT and ADT (35 patients, 49.3%) were retrospectively analyzed. The difference between pre- and Posttreatment primary tumor PSMA expression and serum PSA values measured 4 months after completion of treatment were compared between treatment arms. Correlation between primary tumor metabolic response and serum PSA changes was analyzed. The median duration between pre- and Posttreatment 68Ga-PSMA-PET/CT for the entire patient population was 6.9 months (range, 5.6-8.4 months), and it was similar in both treatment arms. A decrease in primary tumor maximum standardized uptake value (SUVmax) was seen in 66 patients (93.0%), with a median value of 61.2%, which is significantly lower in patients undergoing RT alone than those undergoing RT and ADT (45.1 ± 30.6% vs. 59.1 ± 24.7%; p = 0.004). The complete metabolic response rate was significantly higher in patients undergoing RT and ADT than those treated with RT alone (40% vs. 0%; p < 0.001). Although moderate and positive correlation between pretreatment SUVmax and oosttreatment SUVmax was observed, there was no significant correlation between SUV change and PSA change. For patients treated with RT and ADT, posttreatment SUVmax was significantly lower and SUV change was significantly higher in patients with PSA nadir than in those without. Our preliminary results show that RT, with or without ADT, significantly reduces primary tumor SUVmax and serum PSA levels. Nonetheless, our findings indicate that early treatment response using 68Ga-PSMA-PET/CT is not feasible for those treated with RT alone, and it may only be useful in better distinguishing patients with and without PSA nadir for those who received both RT and ADT.

High Complete Metabolic Response Rates with Epcoritamab SC + GemOx in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for Autologous Stem Cell Transplant: Updated Results from Epcore NHL-2

High Complete Metabolic Response Rates with Epcoritamab SC + GemOx in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for Autologous Stem Cell Transplant: Updated Results from Epcore NHL-2

Results from the Epcore NHL-2 Trial Arm 8: Epcoritamab SC + R-Mini-CHOP Leads to High Complete Metabolic Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Ineligible for Full-Dose R-CHOP

Results from the Epcore NHL-2 Trial Arm 8: Epcoritamab SC + R-Mini-CHOP Leads to High Complete Metabolic Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Ineligible for Full-Dose R-CHOP

DA-EPOCH-R for High Grade B-Cell Lymphoma Patients with MYC and BCL2 and/or BCL6 Rearrangements: Clinical Results of the Induction Phase of the HOVON-152 Trial

Introduction Patients (pts) with high grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 gene rearrangements (double hit and triple hit (DH/TH)) have poor outcomes to standard R-CHOP. Retrospective studies reported improved disease-free survival (DFS) through intensification with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). This regimen was studied in a small prospective trial including 24 DH/TH and 19 single MYC rearranged (SH) lymphomas (Dunleavy, Lancet Haematol 2019). No prospective studies evaluating DA-EPOCH-R exclusively for pts with DH/TH HGBL have been reported. The HOVON-152 trial aimed to improve outcomes in untreated DH/TH HGBL pts by investigating the efficacy of the immune checkpoint inhibitor nivolumab as consolidation treatment in pts achieving complete metabolic response (CMR) after DA-EPOCH-R induction. Here, we present the efficacy and safety profile of the induction phase with DA-EPOCH-R. Methods HOVON-152 is a prospective, multi-center, single arm phase II trial. Inclusion criteria were pts with newly diagnosed HGBL-DH/TH (according to the WHO 2016 classification), age ≥ 18 years, WHO performance status (PS) 0-3 and Ann Arbor stage II-IV. During the screening period for rearrangement status, pts could receive 1 cycle of R-CHOP or DA-EPOCH-R, followed by 5 cycles of DA-EPOCH-R. All pts received intrathecal CNS prophylaxis. All diagnostic lymphoma samples were centrally reviewed. PET-CT scans were performed at diagnosis, after 3 cycles and at end-of-induction (local review, central review will be reported at the conference). Pts in CMR after induction treatment (Deauville 1-3 or a negative lymphoma biopsy in case of Deauville 4) proceeded to nivolumab consolidation (480 mg every 4 weeks for one year). The HOVON-152 aimed to improve 12 months DFS of pts in CMR after induction from an expected 70% to 85% with nivolumab consolidation. Secondary objectives included evaluation of response rates, overall survival (OS) and safety. With a power of 0.90 a sample size of 97 pts was calculated. Here, we report efficacy (CMR rate) and safety of DA-EPOCH-R induction treatment. Logistic univariate analysis is used to analyze baseline characteristics associated with response. Adverse events (AEs) were defined according to the common terminology criteria for adverse events (CTC AE 5.0), counted by the highest grade per system organ class per patient. Results From August 2018 - March 2022, 97 pts have been enrolled (study inclusion completed). One patient was excluded due to CNS localization. The median age was 62 years (range 35-79); 90 (83%) pts had stage III-IV disease and 52 (54%) had (intermediate-)high international prognostic index (IPI) (Table 1). Central pathology review confirmed DH/TH in all pts. 65 pts (67%) had a BCL2 DH, 11 (12%) a BCL6 DH and 16 (17%) a TH. Dose adjustments were performed conform protocol. The maximum dose-level (DL) achieved was DL1 in 41 (43%), DL2 in 22 (23%), DL3 in 25 (25%), DL4 in 7 (7%) and DL5 in 1 (1%) of the pts. Vincristine dose was reduced in 28/81 (35%) pts. After DA-EPOCH-R induction, 63/96 (66%, 95% CI 55-75%) pts achieved CMR. WHO PS 2-3 (odds ratio (OR) 0.15, 95% CI 0.03-0.85, p=0.03), elevated LDH (OR 0.24, 95%CI 0.10-0.59, p=0.002) and bulky disease defined as ≥10 cm mass (OR 0.23, 95%CI 0.09-0.56, p=0.001), were significantly associated with a lower chance of achieving CMR. During treatment, 7 (7%) pts experienced a grade 5 AE (ileus, intestinal perforation, multi-organ failure/sepsis). Thereof, 4 patients died during DA-EPOCH-R and 3 patients died after DA-EPOCH-R. 31 (32%) experienced a grade 4 AE (e.g. sepsis, perforation, hemorrhage, thrombocytopenia and neutropenia), 21 (22%) a grade 3 AE (e.g. anemia, mucositis, infections and electrolyte disturbances) and 16 (17%) pts a grade 2 AE. Conclusion We report the largest prospective series of DH/TH HGBL patients treated with DA-EPOCH-R. DA-EPOCH-R induction was feasible, with toxicity and dose adjustments as previously described. The observed CMR rate of 66% was lower than previously reported in a prospective cohort of mixed DH/TH and SH patients (74%). For patients achieving CMR, the nivolumab consolidation phase is ongoing. Translational side studies investigating predictive factors to identify patients not achieving CMR are ongoing. For these patients, novel strategies to improve first-line treatment are warranted.

Results of the Phase II of Epirchop Study, Evaluating the Efficacy of Tazemetostat in Combination with R-CHOP in Elderly Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL): A Lysa Study

Introduction: Tazemetostat (TAZ) is a selective oral EZH2 inhibitor with a favorable safety profile and activity in pts with either EZH2wild type or mutant B-cell NHL. In the phase I part of Epi-RCHOP study, we reported that R-CHOP plus TAZ (Taz-RCHOP) was well tolerated with safety and PK results comparable to R-CHOP alone, and the RP2D of TAZ in combination with RCHOP was consistent with TAZ monotherapy (800mg BID). We report here the efficacy results of the phase II TAZ R-CHOP study (Epi-RCHOP, NCT02889523), in pts 60-80y with newly diagnosed DLBCL. Methods: Pts received 6 R-CHOP every 21 days in combination with continuous TAZ at 800 mg BID, plus 2 cycles of TAZ and R (cycle 7 and 8). Prophylaxis with G-CSF, valaciclovir and trimethoprim sulfamethoxazole were strongly recommended. Primary endpoint was PET-based complete metabolic response rate (CR, Lugano 2014) at end of study treatment (EOT, i.e 8 cycles or at time of permanent treatment discontinuation) (data cut-off was January 30, 2023). Sample size calculation was made with the expectation of an increase of 10% in CR, with an H0 hypothesis of 70% and an H1 assumption of 80%, leading to a theorical sample size of 122 pts, assuming a drop out of 5%. The efficacy set correspond to pts who signed an informed consent and received at least one dose of TAZ. Pts without response assessment (no matter the reason) were considered non-responders. Key secondary objectives were progression free and overall survival. A sensitivity analysis was performed excluding pts who withdrawn their consent (N=112). Analyses were conducted using SAS® version 9.3. Results: From July 31, 2020 to July 18, 2022, 122 pts were enrolled in 27 LYSA centers. Median age was 70 years (60-80), 57% were female, 12% had an ECOG-PS2+, 70.5% a stage IV disease and 19.7% stage III, 66% elevated LDH, 73.8% an IPI of 3-5. Mutational profile was available for 76 pts, of whom 10 (13%) had an EZH2 mutations and 26 (34%) and EZB profile as assessed with LymphGen classifier. One hundred pts (82%) received 8 cycles and 22 had a premature treatment discontinuation (PTD), 12 (9.8%) during the first 2 cycles and 10 (8.2%) between cycle 3 and 8. Reasons for PTD were: consent withdrawal (N=10, including 7 during cycle 1 &amp; 2), adverse events (AE, N=6, including 2 treatment related), death (N=2, both due to septic shock), protocol deviation (N=2), progressive disease (N=1) or physician decision (N=1). Overall, the median percentage of TAZ dose received was 98.4% (mean 77.2%, Q1: 61%; Q3: 100%), and AE led to TAZ interruption in 4.1%, discontinuation in 2.8% and dose reduction in 2.4% of the cases. Mean time between cycles was 21.5 days. In oct 2020, after the inclusion of 22 pts, recommendation to cap vincristine at 1mg was done, due to an excess of constipation. At end of treatment or PTD, 92/122 pts (75.4%, IC95: 66.8-82.8%) achieved CR, 8 (6.6%) PR, 5 (4.1%) had a PD, 2 (1.6%) had died (septic shock) and 15 (12.3%) were not evaluated and considered as non-responders. The primary objective was not met in this efficacy set, with a CR of 75.4% (lower than the H1 at 80%). The sensitivity analysis, excluding the 10 pts that withdrawn their consent (all non-evaluated), showed a CR rate of 82.1% (92/112, IC95: 73.8-88.7%) and PR rate of 7.1%. After a median follow-up of 18.5 months (Range = [0.2; 28.1]), 17/122 pts had a relapse/progression (13.9%) and 12 had died: 4 due to lymphoma, 3 to COVID-19, 4 to AE (2 septic shock, 1 acute myeloid leukemia and 1 heart failure), 1 unknown cause (in CMR). The estimated 18m PFS and OS were 77.7% (IC95: 67.5-85.1%) and 88.8% (IC95: 79.9-93.9%) respectively. Most frequent AE were: neutropenia (53%), anemia (51%), nausea (47%), asthenia (42%), peripheral neuropathy (37%), gastro-intestinal hypomotility (35%), weight loss (28%), vomiting (24%), thrombocytopenia (24%). AE of grade 3 or more occurred in 73% of the pts and were mainly hematological AE with neutropenia (48%, including 6% of febrile neutropenia), anemia (23%), thrombocytopenia (17%) and gastro-intestinal disorder (overall 10.7%). Red blood cell and platelets transfusions were administered in 31% and 11.5% of the pts respectively. Conclusion: R-CHOP plus TAZ is doable. Efficacy results in this trial conducted during the COVID pandemic in a particularly challenging population, suggest that the combination warrant further investigation including correlative studies with molecular subclassification that will be presented.

The phase 2 LYSA study of prednisone, vinblastine, doxorubicin, and bendamustine for untreated Hodgkin lymphoma in older patients

AbstractOlder patients with classical Hodgkin lymphoma (cHL) require more effective and less toxic therapies than younger patients. In this multicenter, prospective, phase 2 study, we investigated a new firstline therapy regimen comprising 6 cycles of prednisone (40 mg/m2, days 1-5), vinblastine (6 mg/m2, day 1), doxorubicin (40 mg/m2, day 1), and bendamustine (120 mg/m2, day 1) (PVAB regimen) every 21 days for patients with newly diagnosed cHL aged ≥61 years with an advanced Ann Arbor stage. A Mini Nutritional Assessment score ≥17 was the cutoff value for patients aged ≥70 years. The primary end point was the complete metabolic response (CMR) rate after 6 cycles. The median age of the 89 included patients was 68 years (range, 61-88 years), with 35 patients (39%) aged ≥70 years. Seventy-eight patients (88%) completed the 6 cycles. The toxicity rate was acceptable, with a 20% rate of related serious adverse events. CMR was achieved by 69 patients (77.5%; 95% confidence interval [CI], 67-86). After a median follow-up of 42 months, 31 patients progressed or relapsed (35%), and 24 died (27%) from HL (n = 11), toxicity during treatment (n = 4), secondary cancers (n = 6), or other causes (n = 3). The 4-year progression-free survival (PFS) and overall survival rates were 50% and 69%, respectively. Multivariate analysis showed that liver involvement (P = .001), lymphopenia (P = .001), CRP (P = .0005), and comedications (P = .003) were independently associated with PFS. The PVAB regimen yielded a high CMR rate with acceptable toxicity. Over long-term follow-up, survival end points were influenced by unrelated lymphoma events. This trial was registered at www.clinicaltrials.gov as #NCT02414568 and at EudraCT as 2014-001002-17.

Glofitamab Plus Polatuzumab Vedotin Continues to Demonstrate Frequent and Durable Responses and Has a Manageable Safety Profile in Patients with ≥2L Relapsed/Refractory DLBCL, Including HGBCL, and in Patients with Prior CAR T-Cell Therapy: Updated Results from a Phase Ib/II Study

Background: Glofitamab (Glofit) is a CD20xCD3 bispecific antibody which engages and redirects T cells to eliminate B cells. Glofit monotherapy recently received FDA and EMA approval for treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥2 prior lines of therapy. Polatuzumab vedotin (Pola) is a CD79b-targeted antibody-drug conjugate that has a complementary mode of action to Glofit, with little toxicity overlap. In this open-label, multicenter Phase Ib/II study (NCT03533283), Glofit+Pola demonstrated durable responses and a manageable safety profile in patients with R/R DLBCL (Hutchings et al. ICML 2023). We present updated results with longer follow-up in patients with R/R DLBCL, including high-grade B-cell lymphoma (HGBCL), and in patients with prior chimeric antigen receptor (CAR) T-cell therapy. Methods: Patients receivedobinutuzumab 1000mg on Cycle (C) 1 Day (D) 1 to mitigate the risk of severe cytokine release syndrome (CRS). Pola 1.8mg/kg was given on C1D2 and D1 of C2-6 (21-day cycles). Glofit was given with step-up dosing in C1 (C1D8 2.5mg; C1D15 10mg; D1 of C2-12 10/30mg) for up to 12 cycles. The primary objective was to establish the recommended Phase II dose of Glofit when combined with Pola; this was previously identified as 30mg based on the dose-escalation phase and the NCT03075696 study (Hutchings et al. ASH 2021; Hutchings et al. J Clin Oncol 2021). Results: At the data cut-off (Jan 25, 2023), 111 patients had received ≥1 dose of study drug (safety population). The median age was 68 (range 23-82) years; 61.3% of patients were male; 50.5% had DLBCL not otherwise specified (NOS), 24.3% had HGBCL, 23.4% had transformed follicular lymphoma (trFL), and 1.8% had primary mediastinal large B-cell lymphoma (PMBCL). Most patients were refractory to their last prior therapy (71.2%). Median number of prior lines of therapy was 2 (range 1-7; 61.3% of patients had received ≥2), 24.3% had received prior CAR T-cell therapy. The overall response rate (ORR) in 109 efficacy-evaluable patients was 78.0%, with a complete metabolic response (CMR) rate of 56.0%. In patients with DLBCL NOS (n=56), ORR and CMR rate were 85.7% and 60.7%, respectively. In patients with trFL (n=26), ORR and CMR rate were 76.9% and 53.8%, respectively. In patients with HGBCL (n=25), ORR and CMR rate were 60.0% and 44.0%, respectively. The two patients with PMBCL achieved a CMR. In patients who had prior CAR T-cell therapy (n=27), ORR was 77.8% and CMR rate was 44.4%. In 61 patients who had a complete response, estimated 6- and 12-month duration of complete response (DOCR) rates were 89.2% and 73.1%, respectively ( Figure). Estimated 6-month and 12-month DOCR rates in patients with DLBCL NOS (n=34) were 84.2% and 59.2%, respectively; with trFL (n=14), were 92.9% and 85.7%; with HGBCL (n=11), both were 100%. In patients with PMBCL (n=2), the estimated 6-month DOCR was 100%. With a median follow-up of 13.0 months, median progression-free survival was 10.4 (95% confidence interval [CI]: 5.8-19.0) months ( Figure). Median overall survival was not reached after a median survival follow-up of 15.2 months. In 108/111 patients who had received ≥1 dose of Glofit, the most common adverse event (AE) was CRS (45.4% [Grade 1, 30.5%; Grade 2, 13.9%]). One patient had Grade 5 CRS in the context of an unresolved infection; the patient declined further CRS management when the event was Grade 3. Of 111 safety-evaluable patients, 27 (24.3%) had peripheral neuropathy (all Grade 1/2, 8 events were resolved). Glofit-related AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 3 patients and were all Grade 1/2. Grade 3/4 AEs were reported in 61.3% of patients, with neutropenia the most common event (29.7%). Serious AEs occurred in 58.6% of patients, and Grade 5 AEs occurred in 6.3% of patients (5/7 events due to COVID-19); 9.9% of patients discontinued any treatment due to an AE (6.3% discontinued Pola; 9.0% discontinued Glofit). Conclusions: Glofit+Pola demonstrated high response rates and durable responses in heavily pre-treated patients, the majority of whom were refractory to their last prior therapy, across all histologies, including in patients with HGBCL and those with prior CAR T-cell therapy. The safety profile was manageable and consistent with the individual drugs. The rates of CRS events and AEs potentially consistent with ICANS were low. Updated data will be presented.

Epcoritamab SC + GemOx Leads to High Complete Metabolic Response Rates in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for Autologous Stem Cell Transplant: Updated Results from Epcore NHL-2

Background: Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who fail or are ineligible for autologous stem cell transplant (ASCT) have poor outcomes with standard chemotherapy, and novel, effective therapeutic options are needed. A retrospective analysis showed that treatment with rituximab and gemcitabine + oxaliplatin (GemOx) in a transplant-ineligible population resulted in a complete response rate of 33% in the overall population; among patients refractory to previous therapy, 10% achieved complete response (Cazelles et al, Leuk Lymphoma 2021). Epcoritamab, a subcutaneously administered (SC) CD3xCD20 bispecific antibody, has demonstrated deep, durable responses with a manageable safety profile as a single agent in patients with R/R DLBCL. Based on these data, epcoritamab SC was approved by the US FDA for the treatment of adults with R/R DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma, after ≥2 lines of systemic therapy. In the EPCORE ™ NHL-2 phase 1/2 trial (NCT04663347), epcoritamab + GemOx treatment showed encouraging preliminary efficacy with overall expected and manageable safety in patients with R/R DLBCL who failed or were ineligible for ASCT. Here, we present updated results with longer follow-up. Methods: Adults with R/R CD20 + DLBCL who had failed or were ineligible for ASCT were enrolled. Patients received epcoritamab SC in 28-d cycles (Cs) as follows: weekly, C1-3; every 2 weeks, C4-9; every 4 weeks, C≥10 until progressive disease or unacceptable toxicity. Patients received GemOx every 2 weeks in C1-4. Step-up epcoritamab dosing (step-up doses 1 and 2 followed by 48-mg full doses) and corticosteroid prophylaxis were required in C1 to mitigate CRS. The primary endpoint was overall response rate (ORR) as assessed by PET-CT per Lugano criteria. Results: A total of 34 patients (median age, 71 y; range, 47-87) with a median follow-up of 20.3 mo (range, 1.0+ to 26.8) received epcoritamab SC 48 mg + GemOx on or prior to August 24, 2022. At the data cutoff date (April 24, 2023), treatment was ongoing in 35% of patients. A majority of patients (68%) had stage III or IV disease, 53% had primary refractory disease, 38% were refractory to ≥2 consecutive lines of prior therapy, and 79% were refractory to the last line of therapy. The median number of prior lines of treatment was 2 (range, 1-6); 11 patients (32%) had 3 or more prior lines of treatment. A total of 7 patients (21%) had prior CAR T, and 5 patients (15%) had previously received ASCT. The most common treatment-emergent AEs (TEAEs) of any grade (G) were thrombocytopenia/decreased platelet count (68%), diarrhea (59%), anemia (56%), CRS (56%), and neutropenia/decreased neutrophil count (56%). This trial was conducted amid the COVID-19 pandemic and 32% of patients experienced COVID-19. Most CRS events were low grade (53% G1-2; 3% G3) and primarily occurred following the first full dose (C1D15); no incidence of CRS resulted in epcoritamab discontinuation, and all events resolved. ICANS (G1) was reported in 1 patient; this event resolved in 2 d. No clinical tumor lysis syndrome was reported. There were 10 G5 TEAEs; in 2 cases, the contribution of epcoritamab could not be ruled out by the investigator (small intestinal perforation and multiple organ dysfunction syndrome; both patients had multiple confounding factors). The ORR was 91% (31/34), with 59% (20/34) of patients achieving complete metabolic response (CMR). Median times to response and CMR were 1.5 mo and 2.6 mo, respectively. The ORR and CMR rates were 94% and 39% among patients with primary refractory disease, 89% and 78% among patients ≥75 y of age, and 90% and 50% among patients with IPI ≥3 ( Table). Response rates were comparable for patients with and without prior CAR T treatment: ORR of 86% and CMR rate of 57% among patients with prior CAR T; ORR of 93% and CMR rate of 59% among CAR T-naive patients. Conclusions: Epcoritamab SC + GemOx led to high CMR rates in this difficult-to-treat R/R DLBCL population ineligible for transplant with high unmet medical need. No new safety signals were identified, and the safety profile was consistent with those of the individual drugs. These data are encouraging and underline the versatility of epcoritamab SC for the treatment of R/R DLBCL. Additional data and subgroup analyses will be presented.

Epcoritamab SC + R-Mini-CHOP Leads to High Complete Metabolic Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Ineligible for Full-Dose R-CHOP: First Disclosure from Arm 8 of the Epcore NHL-2 Trial

Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard of care for previously untreated (1L) diffuse large B-cell lymphoma (DLBCL); however, some patients are not candidates for full-dose R-CHOP due to advanced age, frailty, or underlying comorbidities. For these patients, various attenuated treatment regimens have been evaluated, with low-dose R-CHOP (R-mini-CHOP) being widely adopted as a standard 1L regimen. However, outcomes are suboptimal, with overall response rates (ORRs) and complete metabolic response (CMR) rates around 70% and 40-60%, respectively, and a 2-y progression-free survival rate of only 47%, leaving substantial room for improvement. Epcoritamab, a subcutaneous (SC) CD3xCD20 bispecific antibody, was approved by the US FDA for the treatment of adults with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. In the 1L setting in patients with high-risk DLBCL, epcoritamab SC with full-dose R-CHOP had a favorable safety profile and showed promising efficacy, including an ORR of 100% (Falchi et al, ASCO 2023). Here we report initial data from arm 8 of the EPCORE™ NHL-2 study (NCT04663347; phase 1/2) evaluating epcoritamab SC + R-mini-CHOP in 1L DLBCL. Methods: Adults with 1L CD20 + DLBCL who were not considered candidates for full-dose R-CHOP due to age ≥75 y or age ≥65 y with comorbidities (reduced left ventricular ejection fraction, history of myocardial infarction [&amp;gt;6 mo prior to enrollment], exertional chest pain, arrhythmia [grade ≤2], hypertension requiring treatment, or diabetes) were enrolled. Patients received epcoritamab SC (QW, cycles 1-2 [21 d each]; Q3W, cycles 3-6 [21 d each]; Q4W, cycles 7-8 [28 d each]) with R-mini-CHOP in cycles 1-6 (Q3W). A safety run-in was conducted to confirm acceptability of the safety profile. The primary endpoint of arm 8 was ORR as assessed by PET-CT per Lugano criteria. Results: As of April 24, 2023, 28 patients had received epcoritamab SC 48 mg + R-mini-CHOP. The median age was 81 y, 14 patients (50%) had IPI 3-5, 10 patients (36%) had bulky disease (&amp;gt;6 cm), and 15 patients (54%) had stage IV disease. At the data cutoff, median follow-up was 6.2 mo (range, 2.5+ to 11.7), with 9 patients (32%) having completed treatment and 15 patients (54%) still on treatment. R-mini-CHOP median relative dose intensity was ≥94%. There were no dose-limiting toxicities. The most common treatment-emergent AEs (TEAEs) of any grade were cytokine release syndrome (CRS; 43%), neutropenia (32%), fatigue (25%), anemia (21%), constipation (21%), and hypokalemia (21%). TEAEs decreased over time; 3 patients (11%) discontinued epcoritamab SC due to TEAEs. One grade 5 TEAE (cytomegalovirus infection reactivation) was recorded. CRS events were primarily low grade (grade 1-2: 39%, grade 3: 4%, grade ≥4: 0%), timing was predictable, and a majority of events were observed after the first full dose (cycle 1, day 15); all events resolved, with a median time to resolution of 3 d (range, 1-7). No ICANS events were reported. All 20 efficacy-evaluable patients had a response (ORR, 100%), with 17 patients (85%) achieving CMR. Median time to response was 1.4 mo ( Figure). At both month 6 and month 9, most patients who achieved CMR remained in CMR, suggesting durability of response. The study is ongoing and updated results will be presented. Conclusions: Epcoritamab SC + R-mini-CHOP showed encouraging efficacy with high response rates in patients with 1L DLBCL who cannot tolerate full-dose R-CHOP, including elderly, frail, and high-risk patients. There were no new safety signals, and findings were consistent with previously reported data, supporting the feasibility of the combination. These results warrant further investigation of epcoritamab-based therapies in 1L DLBCL.

A Prospective, Phase-II Study to Evaluate the Efficacy and Safety of Obinutuzumab, Ibrutinib, and Venetoclax (GIVeRS) in Patients with Richter's Syndrome

Background: Richter's syndrome (RS) is an aggressive histologic transformation of chronic lymphocytic leukemia (CLL), most commonly to diffuse large B-cell lymphoma (DLBCL). RS is characterized by a rapid clinical course, low responses to therapy, and poor long-term survival. Chemoimmunothreapy for RS achieves overall response rates of 40% to 60%, and median progression-free survival (PFS) and overall survival (OS) of 3 to 10 months and 6 to 21 months, respectively. More recently, single targeted agents of either ibrutinib or venetocolax have been shown some clinical activity in RS. Furthermore, ibrutinib combined with venetoclax with or without anti-CD20 antibodies has a synergistic activity in CLL, resulting in deep and prolong responses along with a good safety profile. Methods: This is a prospective phase 2, open-label, non-randomized, single-arm, multi-center study aimed to assess the efficacy and safety of ibrutinib, venetoclax, and obinutuzumab in treatment-naïve or relapsed/refractory patients with biopsy-confirmed RS to DLBCL (NCT04939363). The experimental regimen consisted of 12 months of fixed-duration treatment with obinutuzumab, ibrutinib, and venetoclax. Obinutuzumab was administered at a dose of 100 mg intravenously on day 1, 900 mg on day 2, and then 1000 mg on day 8 and 15 of cycle 1. On day 1 of the subsequent five cycles, obinutuzumab at a dose of 1000 mg was administered. Ibrutinib was administered at a dose of 560mg orally daily initiated together with the first obinutuzumab infusion on day 1 of cycle 1 and was continued throughout the 12 treatment 28-day cycles. Venetoclax was given at a dose of 400 mg orally daily for 12 treatment cycles after an accelerated ramp-up phase from day 15 in cycle 1. The primary endpoint was investigator-assessed overall response rate (ORR) defined as the proportion of patients who achieve complete metabolic response (CR) and partial metabolic response (PR) determined by PET-CT imaging at 6 months per Lugano 2014 criteria. Other key endpoints included; investigator-assessed ORR at 3 and 12 months, PFS, Duration of response (DOR), OS, and safety. Results: From August 2021 until the data cut-off on July 20, 2023, a total of 10 patients with RS were enrolled. Median age was 76.0 (range, 62‒88) years and 70% were male. Six patients were treatment-naïve, 4 had relapsed/refractory RS, 50% had extra-nodal disease, 70% had elevated LDH, 70% were double or triple expressors, and the median number of prior therapies among the R/R patients was 1 (Table 1). Median follow-up was 255 days (95% CI, 158.7-351.3), median treatment duration was 160 days (range: 29-362) and treatment is still ongoing in 3 patients. At 3 and 6 months, the ORRs were 70.0% (7/10) and 22.2% (2/9), respectively, and CR rates (CRRs) were 40.0% (4/10) and 11.1% (1/9), respectively. At the data cutoff, 6/10 (60.0%) patients progressed and 5/10 (50.0%) died. The median PFS was 162 days (95% CI, 66.9-257.1), median DOR 272 days, and median OS was 228 days (95% CI: 184.2-271.8). The causes of death included RS in 2 patients and one case each of Covid-19, secondary malignancy, and general deterioration. Most common related treatment-emergent AEs (TEAEs) of all grades were neutropenia 40%, thrombocytopenia 50%, diarrhea 40%, and skin rash 50%, 2 patients developed Covid-19 who recovered during the protocol. None of the patients developed tumor lysis syndromes. Conclusions: In patients with RS triplet treatment with ibrutinib, venetoclax, and obinutuzmab was well tolerated, achieved high rates of early metabolic response (ORR-70% and CRR-40%) at 3 months. Given the high early response rate but subsequent progression, this triplet therapy may serve as a bridge to consolidation with cellular therapy.

Glofitamab Plus R-CHOP Induces High Response Rates with a Manageable Safety Profile in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A 12-Month Analysis from a Phase Ib Study

Background: Over a third of patients (pts) with DLBCL do not respond or relapse after first-line (1L) treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; Sarkozy and Sehn. Ann Lymphoma 2019); these pts have limited curative options. Glofitamab (Glofit) is a T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format that allows bivalent binding to CD20 on B cells; this enables combination with anti-CD20 antibodies, including rituximab. Glofit monotherapy has shown durable responses in pts with relapsed/refractory DLBCL (Dickinson et al. NEJM 2022). In the safety run-in and expansion phases of the ongoing NP40126 trial (NCT03467373), Glofit + R-CHOP demonstrated promising efficacy and manageable safety in pts with 1L DLBCL (Topp et al. ASH 2022). Here, we report durability of response beyond 12 months in Glofit + R-CHOP-treated pts with 1L DLBCL from the NP40126 trial. Methods: Pts received R-CHOP for 6-8 three-weekly cycles. Intravenous Glofit was given with step-up dosing during Cycle (C)2 (Day [D]8, 2.5mg; D15, 10mg) and at the target dose (30mg) from C3D8 onwards. Glofit maintenance was allowed for up to one year. Efficacy was analyzed in all pts who had been on the study long enough to have a protocol scheduled end-of-treatment response assessment. Safety was analyzed in all pts who received at least one dose of any study drug. Response was assessed by PET-CT using Lugano criteria (Cheson et al. JCO 2014). Cytokine release syndrome (CRS) events were graded using the American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019) and other adverse events (AEs) by the Common Terminology Criteria for Adverse Events (v4.0). Hospitalization was not mandated for Glofit. Results: As of April 4, 2023, 56 pts were enrolled in this cohort. Median age was 68 years (range: 21-84), 54 pts (96.4%) had Ann Arbor stage III/IV disease, and median International Prognostic Index (IPI) score was 3 (IPI 1: 3.6% [2/56], IPI 2: 33.9% [19/56], IPI 3: 35.7% [20/56], IPI 4: 23.2% [13/56], IPI 5: 3.6% [2/56]). The cell of origin was germinal center B-cell (GCB) in 25 (44.6%) pts and non-GCB in 11 (19.6%) pts. After 17.1 (range: 0-26) months of median follow-up, the best overall response rate was 92.9% (52/56) and the complete metabolic response (CMR) rate was 83.9% (47/56). Median time to CMR was 1.8 months (95% confidence interval [CI]: 1.6-4.7). Most CMRs (44/47; 93.6%) were ongoing at data cut-off ( Figure). Among complete responders, the Kaplan-Meier estimated probability of ongoing responses at 12 months was 91.5% (95% CI: 82.2-100). Median duration of response and duration of complete response were not reached at data cut-off. The incidence of AEs and serious AEs (SAEs) were similar compared with earlier analyses. Grade (Gr) ≥3 AEs occurred in 42 (75.0%) pts and Gr ≥3 AEs related to Glofit in 14 (25.0%) pts. SAEs were reported in 20 (35.7%) pts and SAEs related to Glofit in six (10.7%) pts. Gr 5 AEs were reported in four (7.1%) pts (COVID-19 pneumonia, n=3; infusion related reaction associated with rituximab, n=1). AEs leading to dose interruption of Glofit occurred in 12 (21.4%) pts. Median dose intensity was 100% for all R-CHOP components. AEs leading to discontinuation of Glofit occurred in one (1.8%) patient. CRS events were reported in six (10.7%) pts: Gr 1, n=4; Gr 2, n=2; no Gr 3/4 CRS events were reported. All CRS events occurred during C2-3. Tocilizumab was used in two (33.3%) pts with CRS. Neurologic AEs (NAEs) occurred in 23 (41.1%) pts (most common NAEs (&amp;gt;5%) were peripheral neuropathy, n=7 [12.5%]; paraesthesia, n=5 [8.9%]; insomnia, n=4 [7.1%]; headache, n=3 [5.4%]); Gr 3 NAEs included cerebrovascular accident (n=1) and herpes zoster (n=1). No Glofit-related NAEs consistent with immune effector cell-associated neurotoxicity syndrome were reported. Neutropenia was reported in 26 (46.4%) pts (Gr ≥3 neutropenia: Gr 3, n=5; Gr 4, n=19). Infections and infestations were reported in 27 (48.2%) pts (of which the majority were Gr ≤2 [17/27]); Gr 3, n=7; Gr 5, n=3. Conclusions: Glofit + R-CHOP had a manageable safety profile with a low incidence of CRS, and continued to demonstrate durable responses with an improved CMR rate since the last data cut-off. These findings support the potential for favorable long-term outcomes with Glofit + R-CHOP as 1L treatment of DLBCL. Further analyses, including circulating tumor DNA data, will be presented.

Golcadomide (GOLCA; CC-99282), a Novel CELMoD Agent, Plus R-CHOP in Patients (pts) with Previously Untreated Aggressive B-Cell Lymphoma (a-BCL): Safety and Efficacy Results from Phase 1b Dose Expansion

Introduction Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) relapse after first-line chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). CELMoD agents such as GOLCA potently degrade target proteins Ikaros/Aiolos, resulting in antiproliferative, apoptotic, and immunomodulatory activity. GOLCA preferentially distributes to tissues and lymphoid organs. In a phase 1 study, GOLCA demonstrated a manageable safety profile with promising clinical activity as monotherapy in relapsed/refractory non-Hodgkin lymphoma (Michot et al. Blood 2021). CC-220-DLBCL-001 (NCT04884035) is an ongoing open-label, multicenter, dose escalation and expansion trial to assess safety and preliminary efficacy of CELMoD agents + R-CHOP for untreated a-BCL. GOLCA demonstrated a manageable safety profile in the dose escalation phase (Munoz et al. ICML 2023 abstract 438); we report combined results from the GOLCA dose escalation and expansion phases. Methods Eligible pts were ≥ 18 years, had untreated a-BCL with measurable disease (Lugano 2014), ECOG performance status ≤ 2 and International Prognostic Index (IPI) score 0-5 (2-5 in dose expansion). Pts were treated with R-CHOP plus GOLCA in 21-day (D) cycles (C) for up to 6C, or until disease progression/unacceptable toxicity/study withdrawal/physician decision. During dose escalation, pts received GOLCA at dose levels (DL): 0.2 mg D1-7 (DL-1), 0.4 mg D1-7 (DL1), and 0.4 mg D1-10 (DL2). DL2 met the dose-limiting toxicity threshold and was not continued in the expansion phase. During dose expansion, pts were randomized 1:1 to R-CHOP plus GOLCA at DL-1 or DL1. The primary endpoint for the expansion phase was safety of GOLCA at the recommended phase 2 dose (DL1) (based on adverse events [AEs]); secondary endpoints included overall response rate (ORR) and complete metabolic response (CMR) rate (assessed at end of treatment [EoT] by PET-CT [Lugano 2014]). Circulating tumor DNA (ctDNA) was measured at C1D1, C2D1, C3D1, and EoT using the PhasED-Seq assay. Results Across escalation and expansion, 78 pts were treated (DL-1, n = 35; DL1, n = 37; DL2, n = 6). Median age was 63.0 years, 56.4% were male, most had high-intermediate/high IPI (3-5) score at diagnosis (64.1%), Ann Arbor stage III-IV disease (83.3%), and germinal center B cell as cell of origin (51.3%); 83.3% pts had DLBCL histology. At data extraction (May 25, 2023), across escalation and expansion, 38 pts had treatment ongoing, 31 completed treatment, and 35 continued to follow-up. A total of 3 pts discontinued due to AEs, 1 each at DL-1, DL1, and DL2. In the safety population (n = 78), median GOLCA relative dose intensity (RDI) was 99.4%; 82.1% of pts received RDI ≥ 85%. RDI for CHOP components was &amp;gt; 90%. A total of 73 (93.6%) pts had ≥ 1 treatment-emergent AE (TEAE); 70 (89.7%) pts had ≥ 1 TEAE considered related to GOLCA; 65 (83.3%) pts had ≥ 1 grade 3/4 TEAE, 62 (79.5%) pts had ≥ 1 grade 3/4 TEAE considered related to GOLCA. The most frequently occurring grade 3/4 TEAEs were neutropenia (76.9%) and thrombocytopenia (32.1%) ( Table). A total of 30 (38.5%) pts had serious TEAEs, most frequently febrile neutropenia (preferred term: 11 pts, 14.1%); 12 (15.4%) pts had serious TEAEs of infection or infestation (system organ class); 6 pts (7.7%) had venous thromboembolisms considered related to GOLCA (4 deep vein thrombosis, 1 superficial thrombosis, 1 pulmonary embolism). Treatment-related AEs leading to GOLCA dose reduction or discontinuation occurred in 11 (14.1%) pts and 6 (7.7%) pts, respectively. After a median follow-up time of 4.1 months (range 0.3-12.3) and among all treated pts with EoT response available, 21/25 had CMR; together, 14/14 pts who received GOLCA 0.4 mg (DL1 and DL2) achieved CMR at EoT ( Figure). Among efficacy-evaluable pts (n = 56), ORR was 91.1% (95% CI 80.4-97.0). Pts treated with GOLCA at DL-1 and DL1 who were ctDNA high-risk (≥ 2.5 log hGE/mL) responded to study treatment (CMR-PMR) and had early decreases in ctDNA (Kaplan et al. ASH 2023). Conclusions GOLCA demonstrated a manageable safety profile, showed good combinability with R-CHOP, and did not compromise delivery of curative treatment. Efficacy results and substantial ctDNA decrease indicate robust clinical activity in frontline DLBCL, with a high CMR rate at EoT, particularly among patients treated at DL1. Study support Bristol Myers Squibb.

Tazemetostat in Combination with R-CHOP in Patients with High-Risk, Frontline Follicular Lymphoma (Epi-RCHOP): A Phase II Study from the Lysa

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or with R/R FL who have no satisfactory alternative treatment options. We previously reported that the RP2D of TAZ in combination with R-CHOP was 800mg BID in the phase 1 part of Epi-RCHOP study (NCT02889523). Here, we report results of the phase 2 part evaluating TAZ with R-CHOP + rituximab maintenance in a cohort of previously untreated high-risk FL patients. Methods: patients were eligible if aged 18-80 years, had histologically confirmed FL grade 1-3A, high-risk FLIPI (score of 3-5) and were in need of treatment according to GELF criteria. Induction treatment consisted in 6 cycles of RCHOP every 21 days and TAZ 800mg BID every day, starting on day 2 of cycle 1, plus 2 additional 21 days cycles of rituximab+TAZ (cycle 7 and 8). Responses were assessed at end of induction (EOI), and responders then received maintenance 1 (TAZ 6 mo + rituximab 12 mo) and maintenance 2 (12 mo of rituximab alone).The primary efficacy endpoint was PET-based complete response rate based on local assessment at the end of induction or at permanent treatment discontinuation, as determined by Cheson IWG 2014 Lugano Classification (Deauville scale 1-3); in addition bone marrow biopsy (BMB) was mandatory at EOI if involved at baseline and complete metabolic response (CMR) patients with missing assessment at EOI classified as partial responders. Sample size calculation was made with the expectation of an increase of 13% in CR, with an H0 hypothesis of 67% and an H1 assumption of 80%, leading to a theorical sample size of 62 pts, assuming a drop out of 10%. Initial assumption was that CR rate should be &amp;gt;76.4% to consider the combination eligible for further clinical evaluation in high risk FL patients. Results: As of June 14, 2022, 62 patients were enrolled between Aug2020 and Apr2022 across 20 centers (including a drop-out of 12 patients, 70 were enrolled in France, 4 in Belgium). Disease characteristics included: males 61.3%, median age 64.5 years, FLIPI 3/4/5 in 61.3%/32.3%/6.5%, EZH2 mutated 17.3% (n=9/46 assessed had EZH2 mutation; 16 undertermined), BM involvement 68.3%, circulating FL cells in 21%, and increased LDH in 50%. Fifty eight (93%) patients completed induction and initiated maintenance 1, 44 (71%) initiated maintenance 2. Fourteen patients permanently discontinued treatment: 4 before EOI not related to PD (2 COVID19 disease, 1 late onset neutropenia and 1 stopped therapy but accepted FU), and 9 after EOI (5 PD, 2 COVID19 disease, 1 neutropenia, 1 paralytic ileus and 1 patient's refusal). At EOI, 79% (95%CI 66.8; 88.3%) achieved complete metabolic response (CMR) and 16.2% PMR for an overall metabolic response rate of 95.2%, however, according to the stringent protocol definition, 16 patients who achieved CMR had no BMB assessment at EOI and were downgraded to PR leading to 53.2% CR and 41.9% PR rate at EOI. Complete response rates were significantly higher in EZH2 mutants (8/9 CMR 88.9%) versus 17/37 (45.9%) in EZH2 wild-type (WT) patients (Fisher exact test p=0.027). Figure 1 shows the AEs reported by more than 10% of patients. The most common grade 3-4 TEAEs were neutropenia (53.2%, only 3.2% febrile), thrombocytopenia (17.7%), anemia (16.1%). Serious AEs occurred in 14 patients, the two most frequent being Covid19 disease (6.5%) and gastrointestinal hypomotility (6.5%). This latter AE was the most frequent non-hematologic event (40.3%), followed by peripheral neuropathy (35.5%). After amending vincristine dose (Oct2020), 30 digestive AEs were reported (16 related to TAZ, mostly grade 1-2, only 1 grade 3, no sequelae). No SPM was observed. With a median follow-up of 19 months, 7 relapses (5 EZH2 WT and 2 undetermined) including 5 needing subsequent treatment and 2 deaths occurred (1 Covid19 disease, 1 after PD). Median PFS and median DOR were not reached and appeared to be similar irrespective of EZH2 status, 18-months PFS and OS rates were 89.3% and 98.3% respectively. Conclusions: Although the primary endpoint was not met due to missing BM assessments, TAZ + RCHOP combination demonstrated a promising complete metabolic response rate of 79% in this high-risk frontline FL population, with a manageable safety profile, after vincristine dose was reduced.

Real World Data of Axicabtagene Ciloleucel As Second Line Therapy for Patients with Large B Cell Lymphoma: First Results of a Lysa Study from the French Descar-T Registry

Background and Significance: Axicabtagene ciloleucel (axi-cel) has demonstrated superior efficacy as second-line therapy (2L) over standard of care chemo-immunotherapy in transplant-eligible patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). In ZUMA-7 trial, 180 patients were randomized to receive axi-cel in 2L, achieving an estimated 4-year overall survival of 54% after a median follow-up of 47 months. In the ALYCANTE phase II study, 62 transplant-ineligible patients with R/R LBCL were treated with axi-cel as 2L, resulting in a 3-month complete metabolic response rate of 71% with a median progression free survival of 11.8 months. Here, we report the first real-world data of axi-cel as 2L for patients with early R/R LBCL treated in French centers. Study Design and Methods: DESCAR-T is a French nationwide registry collecting real-life data of all patients treated with approved CAR T-cell therapies (NCT04328298). All patients were informed before inclusion in the registry. The goal of the present analysis was to describe patients' characteristics, treatment course, and outcomes of all patients consecutively included in DESCART registry since July 2022, and infused with axi-cel according to the early access program supported by French authorities for patients with LBCL in early relapse (&amp;lt; 1 year) or refractory after a first line treatment. Results: Between July 2022 and March 2023, axi-cel was ordered and leukapheresis was performed for 85 patients. The first axi-cel infusion was performed in September 2022 and enrollment increased rapidly with 51 new patients waiting for a leukapheresis at the time of data cut-off in March 2023. No manufacturing failures occurred, at the data cut-off, 78 patients were infused with axi-cel in 22 centers, and 7 patients died before axi-cel infusion (5 because of progression, 2 from other cause). Among the 78 patients infused, 48 (61.5%) were male, median age was 60 years (range: 23-79), 35% were over 65 years old and 5% over 70 years old. Most patients had primary refractory disease (n = 58, 74.3%), a good performance status (n = 62, 79.5% ECOG 0-1), stage III-IV disease (n = 59, 75.6%) and elevated LDH (n = 48, 61.5%). The median time between leukapheresis and axi-cel infusion was 36 days, and 65 patients (83%) received bridging therapy, primarily immuno-chemotherapy (n = 57, 73%). At the time of lymphodepletion, patients had progressive (n = 35, 54%) or stable disease (n = 6, 9%), with only 23 patients (29%) responding to bridging therapy. The median follow-up since CAR-T-cells infusion was 1.1 month (range: 0-6). Safety information was reported for 65 patients: CRS occurred in 95% of patients, however only 3 patients (&amp;lt;5%) had a grade 3 or higher CRS. Neurotoxicity occurred in 43% of the cases, with 6 patients (9%) presenting grade 3 or higher toxicity. Furthermore, 13 patients (21%) were transferred to intensive care unit. Four patients (5%) died, 3 from lymphoma progression (missing data for the remaining patient). Among the 52 patients with at least 1 month of follow-up: the overall response and complete response rates at 1 month were 76.9% and 57.7% respectively (Figure 1). Conclusion: These preliminary results demonstrated that axi-cel in 2L for R/R LBCL is feasible and safe in real-life for transplant and non-transplant eligible patients. Although follow-up of our population remains short, early assessments of response are in line with those described in ZUMA-7 study. Inclusion in DESCART registry is on-going and updated results with at least 3 months of follow-up since infusion will be presented at the meeting.

Investigating PET Responses to Treatment in Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

There is no standard treatment for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Although response by positron emission tomography (PET) for classic Hodgkin lymphoma (cHL) has allowed for response-adapted treatment, similar approaches for NLPHL have not been developed. This is in part due to the lack of data for PET response to treatment. Therefore, we sought to investigate PET responses to management for NLPHL. We retrospectively identified 47 patients who were diagnosed with or treated for NLPHL between 2001-2018 at a single institution and underwent a staging PET. We recorded clinical data and PET metrics for patients who received various forms of management, including chemotherapy (CT), radiation therapy (RT), combined modality therapy (CMT = CT+RT, with rituximab in a subset), rituximab monotherapy, and observation after excision. Metabolic response was scored according to the Deauville 5-point scale criteria, with complete metabolic response defined as a score 1-3. We identified 47 patients with median age of 26 (IQR = 17-50). They predominantly were male (74.5%) and had early stage (23.4% I, 36.2% II) versus advanced stage (29.8% III, 10.5% IV) NLPHL. The majority of patients had their immunoarchitectural pattern scored (n = 36, 76.6%), with typical pattern (A/B) being the most frequent type (58.3%). The median follow-up was 5.7 years (IQR = 2.3-9.3). Overall survival was 100% at 5 years and 92.3% at 10 years. Primary management included CMT (n = 10, 21.3%; with rituximab in a subset n = 1, 10.0%), CT alone (n = 22, 46.8%; with rituximab in a subset n = 5, 22.7%), RT alone (n = 8, 17.0%), rituximab alone (n = 3, 6.4%), and observation after excision (n = 4, 8.5%). On baseline PET, median SUVmax was 10.7 (range = 1.7-35.4). Of the 10 patients who received CMT, the complete metabolic response rates were 42.9% at interim-chemotherapy PET and 75% at post-chemotherapy PET, which improved to 100% after consolidative radiotherapy. There was no difference in complete metabolic response rate to chemotherapy for typical versus variant pattern (P = 0.60). Of the 22 patients who received CT alone, 66.7% had a complete metabolic response at the interim PET and 72.7% at the end of chemotherapy. For RT, rituximab alone, and observation, the complete metabolic response rates at median 3 months (range 1-5 months) after treatment were 87.5%, 66.7%, 75.0%, respectively. Based on our cohort, we found that patients with NLPHL had a lower complete metabolic response to CT (∼75%) compared to cHL (∼85-90%) and PET-response was improved following RT for those receiving CMT. There was no significant difference in PET-response for those with variant versus typical immunoarchitectural patterns. Our findings will allow for the development of PET response-adapted therapy for NLPHL.

Glofitamab + Pola-R-CHP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL): Results from a phase Ib study.

7549 Background: Polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) has shown a significant progression-free survival benefit versus R-CHOP as first line (1L) therapy for DLBCL (Tilly et al. 2022). Glofitamab is a bispecific antibody with a novel 2:1 (CD20:CD3) format; bivalency for CD20 on B cells enables combination with anti-CD20 antibodies, including rituximab. Glofitamab monotherapy induced durable responses in patients (pts) with relapsed/refractory DLBCL and its incorporation in the 1L setting may further improve outcomes (Dickinson et al. 2022). We present results from the expansion stage of an ongoing Phase Ib study (NCT03467373) of glofitamab (Glofit) + Pola-R-CHP in pts with 1L DLBCL. Methods: Pts received Pola-R-CHP on Day (D) 1 of each 21-day cycle (C; max. 6 cycles) and glofitamab in C2‒C6 (C2 step-up dosing [2.5mg C2D8, 10mg C2D15]; target dose [30mg] C3D8 and onwards). Response was assessed by PET-CT using Lugano criteria (Cheson et al. 2014). Efficacy-evaluable pts were those that reached end of treatment (EOT), progressed or died by data cut-off (EOT population). Cytokine release syndrome (CRS) events were graded by ASTCT criteria (Lee et al. 2019) and other adverse events (AEs) by CTCAE (v4.0). Results: As of Nov 14, 2022, 24 pts had enrolled and received study treatment (safety population). Median age was 65 years (range: 32–85), 96% of pts had stage III–IV disease and median IPI score was 3 (IPI 1: 4% [1/24], IPI 2: 33% [8/24], IPI 3: 38% [9/24], IPI 4: 25% [6/24]). Of 24 pts, 17 were efficacy evaluable. After a median follow up of 5.1 (range: 3–8) months, complete metabolic response rate was 76.5% (13/17) and overall response rate was 100% in the EOT population (best overall response). In safety-evaluable pts, Grade (Gr) ≥3 AEs occurred in 15 (63%) pts and Gr ≥3 AEs related to glofitamab in 9 (38%) pts. One Gr 5 AE was reported (acute respiratory distress syndrome, unrelated to study treatment). Serious AEs (SAEs) were reported in 12 (50%) pts and SAEs related to glofitamab in 4 (17%) pts. AEs leading to glofitamab dose interruption occurred in 5 (21%) pts; median dose intensity was 100% for all Glofit + Pola-R-CHP components. Only Gr 1 CRS (n = 3, 13%) was reported, with no treatment or hospitalization required. Neurological AEs (NAEs) occurred in 11 (46%) pts and were mostly Gr 1/2 (10 pts, 42%); one patient had a Gr 3 NAE (hypomania). No NAEs potentially consistent with immune effector cell-associated neurotoxicity syndrome were reported. Neutropenia was reported in 12 (50%) pts (Gr 3, n = 6; Gr 4, n = 6), febrile neutropenia in 2 (8.3%) pts and Gr 3/4 infection in 4 (17%) pts (Gr 3, n = 2; Gr 4, n = 2). Conclusions: Early data suggest that Glofit + Pola-R-CHP has promising efficacy and a similar safety profile to Pola-R-CHP and Glofit + R-CHOP for 1L DLBCL treatment. Glofit + Pola-R-CHP dose intensity was maintained in all pts. Updated data will be presented. Clinical trial information: NCT03467373 .

18F-FDG PET/CT in therapy response assessment: oligometastatic colorectal cancer

BackgroundColorectal cancer (CRC) is one of the most widespread cancers worldwide, leading to roughly half a million deaths yearly. The European Society for Medical Oncology defined oligometastatic CRC as a disease with few metastases affecting a small number of sites (5 or occasionally more metastases involving up to 3 sites). In addition to colonoscopy, magnetic resonance imaging (MRI), and digital rectal examination in patients with rectal cancer, response monitoring of CRC is commonly carried out by CT imaging. The use of PET for response monitoring has not been adapted into colorectal cancer guidelines until 2021. However, 18F-Fluorodeoxyglucose Positron Emission Tomography Computed Tomography (18F-FDG PET/CT) offers a higher efficiency for assessing treatment outcomes than traditional imaging. This study aims to explore the utility of 18F-FDG PET/CT imaging in the assessment of therapy response in patients with oligometastatic colorectal cancer (OMCRC).ResultsThe study comprised 79 OMCRC patients (35 and 44 patients with synchronous and metachronous metastasis respectively). In synchronous disease patients 18F-FDG PET/CT scan showed significant reduction of mean size and standardized uptake value (SUV) of the primary site lesions and the mean SUV of lymph nodes (LNs) and lung metastases (P = 0.00, 0.00,0.00, and 0.002, respectively) while, metachronous disease patients had significant reduction in the mean size and SUV of LNs (1.8 ± 0.7 & 4.7 ± 1.3 versus 1.1 ± 1.0 & 2.9 ± 3.0, P = 0.001 & 0.00 respectively) and the mean SUV of peritoneal metastases (8.7 ± 4.7 versus 6.8 ± 2.4 P = 0.00). Partial metabolic response (PMR) and stable metabolic disease (SMD) were found in more than half of the patients (58.2%). Complete metabolic response (CMR) and Progressive metabolic disease (PMD), on the other hand, were achieved in 41.8% of patients [17 (21.5%) and 16 (20.3%) patients, respectively] with substantially higher CMR rate in metachronous disease than synchronous disease [14.0 (31.8%) versus 3.0 (8.5%) patients, P = 0.015)].Conclusions18F-FDG PET/CT can be added as a valuable imaging method for identifying responders and non-responders among OMCRC patients, as it optimizes the selection of patients with CRC for local therapy and has a significant impact on directing their therapy course. Oligometastatic colorectal cancer seems to be a controllable disease with hopeful therapy outcomes, particularly for those with metachronous metastases.

Nivolumab and brentuximab vedotin with or without bendamustine for R/R Hodgkin lymphoma in children, adolescents, and young adults

AbstractChildren, adolescents, and young adults (CAYA) with relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) without complete metabolic response (CMR) before autologous hematopoietic cell transplantation (auto-HCT) have poor survival outcomes. CheckMate 744, a phase 2 study for CAYA (aged 5-30 years) with R/R cHL, evaluated a risk-stratified, response-adapted approach with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response. Risk stratification was primarily based on time to relapse, prior treatment, and presence of B symptoms. We present the primary analysis of the standard-risk cohort. Data from the low-risk cohort are reported separately. Patients received 4 induction cycles with nivolumab plus BV; those without CMR (Deauville score >3, Lugano 2014) received BV plus bendamustine intensification. Patients with CMR after induction or intensification proceeded to consolidation (high-dose chemotherapy/auto-HCT per protocol). Primary end point was CMR any time before consolidation. Forty-four patients were treated. Median age was 16 years. At a minimum follow-up of 15.6 months, 43 patients received 4 induction cycles (1 discontinued), 11 of whom received intensification; 32 proceeded to consolidation. CMR rate was 59% after induction with nivolumab plus BV and 94% any time before consolidation (nivolumab plus BV ± BV plus bendamustine). One-year progression-free survival rate was 91%. During induction, 18% of patients experienced grade 3/4 treatment-related adverse events. This risk-stratified, response-adapted salvage strategy had high CMR rates with limited toxicities in CAYA with R/R cHL. Most patients did not require additional chemotherapy (bendamustine intensification). Additional follow-up is needed to confirm durability of disease control. This trial was registered at www.clinicaltrials.gov as #NCT02927769.

Subcutaneous Epcoritamab + R-Dhax/C in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Eligible for Autologous Stem Cell Transplant: Updated Phase 1/2 Results

Background: For patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are eligible for autologous stem cell transplant (ASCT), salvage immunochemotherapy, such as rituximab, dexamethasone, cytarabine, and oxaliplatin or carboplatin (R-DHAX/C), followed by consolidation with high-dose therapy (HDT) and ASCT, is part of the standard of care. However, this treatment plan is unsuccessful in more than half of patients. Novel treatment options are needed to achieve improved responses and more favorable long-term outcomes. Epcoritamab, a subcutaneously administered bispecific antibody that targets CD3 and CD20, has demonstrated clinically meaningful antitumor activity both as a single agent (in the first-in-human phase 1/2 EPCORE NHL-1 trial; NCT03625037) and in combination with standard of care therapies (in the phase 1/2 EPCORE NHL-2 trial; NCT04663347) across B-cell non-Hodgkin lymphoma subtypes. Here we present updated results from arm 4 (epcoritamab + R-DHAX/C) of the EPCORE NHL-2 trial, which is the first clinical study of a bispecific antibody in combination with salvage immunochemotherapy in this high-risk, refractory, ASCT-eligible population. Methods: Adults with R/R CD20+ DLBCL who were eligible for HDT-ASCT were treated with standard R-DHAX/C and subcutaneous epcoritamab (21-d cycles: QW, cycles 1-3). If HDT-ASCT was deferred, patients could continue epcoritamab monotherapy (21-d cycle: QW, cycle 4; 28-d cycles: Q2W, cycles 5-9, and Q4W, cycles ≥10) until disease progression or unacceptable toxicity. Corticosteroid premedication and step-up epcoritamab dosing were required in cycle 1 to mitigate CRS. Response was determined by PET-CT using Lugano 2014 criteria. Results: As of the data cutoff on June 10, 2022, 29 patients had received epcoritamab + R-DHAX/C. The median age was 58 y (range, 28-75), 72% of patients had received 1 prior line of therapy, 28% had received 2 or 3 prior therapies, 34% had transformed disease, 66% had primary refractory disease, and 59% were refractory to their last line of therapy. Three patients had prior CAR T-cell therapy. The median duration of follow-up was 9.2 mo (range, 1.7-14.2). The most common treatment-emergent AEs (TEAEs) of any grade were thrombocytopenia (69%), anemia (45%), CRS (41%), neutropenia (41%), nausea (34%), and fatigue (28%). All CRS events were low grade (grade 1 in 31% of patients, grade 2 in 10% of patients) and resolved, with a median time to resolution of 2 d (range, 1-8). Most CRS events occurred after the first full dose. One patient experienced a grade 2 ICANS event, which resolved but led to treatment discontinuation. No clinical tumor lysis syndrome was observed, and no fatal TEAEs were reported. Of the 26 response-evaluable patients (Figure), 15 (58%) proceeded to transplant per protocol; for these 15 patients, the overall response rate (ORR) with the combination of epcoritamab + R-DHAX/C was 100% (15/15), with 80% (12/15) achieving a complete metabolic response (CMR) and 20% (3/15) achieving a partial metabolic response (PMR). Patients continuing epcoritamab monotherapy instead of HDT-ASCT had an ORR of 64% (7/11), with 45% (5/11) achieving a CMR and 18% (2/11) achieving a PMR. The primary reason for a patient not proceeding to HDT-ASCT was patient choice. Median duration of response was not reached among the 7 responders continuing epcoritamab monotherapy. In the response-evaluable population overall, the ORR was 85% (22/26); rates of CMR and PMR were 65% (17/26) and 19% (5/26), respectively. Conclusions: Subcutaneous epcoritamab in combination with R-DHAX/C demonstrated a manageable safety profile in ASCT-eligible patients with R/R DLBCL. Importantly, no new safety findings were observed. ICANS was rare, and all CRS events were low grade and resolved. High ORRs and CMR rates were observed. As of the data cutoff date, most patients had proceeded to ASCT or remained on epcoritamab in CMR. In conclusion, epcoritamab is well suited for salvage combination therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Subcutaneous Epcoritamab with Rituximab + Lenalidomide in Patients with Relapsed or Refractory Follicular Lymphoma:Phase 1/2 Trial Update

Background: For patients with relapsed or refractory (R/R) follicular lymphoma (FL), therapies such as rituximab + lenalidomide (R2) have demonstrated efficacy and acceptable safety. However, better treatments are needed to help more patients achieve deeper and more durable responses. Epcoritamab is a subcutaneously administered bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on B cells to kill malignant B cells. R2 and epcoritamab have nonoverlapping toxicity profiles and, therefore, may be safely combined. In addition, the immunomodulatory properties of lenalidomide may enhance the therapeutic potential of epcoritamab. Preliminary results from arm 2b of the phase 1/2 EPCORE NHL-2 trial (NCT04663347), which tested R2 and epcoritamab in patients with R/R FL, showed an overall response rate of 93% and a complete metabolic response rate of 61% at the first assessment (6 wk; Falchi et al, ASCO 2022). Here we present updated data on a larger cohort and longer follow-up from arm 2b of EPCORE NHL-2. Methods: Adults with R/R CD20+ FL were treated with subcutaneous epcoritamab 48 mg + standard R2 for 12 cycles of 28 d each. Epcoritamab was dosed as follows: QW, cycles 1 and 2; Q4W, cycles ≥3 up to 2 y. Step-up epcoritamab dosing and corticosteroid prophylaxis were required during cycle 1 to mitigate CRS. PET-CT was used to assess responses per Lugano 2014 criteria. Results: As of the data cutoff date of June 10, 2022, 62 patients had received epcoritamab (48 mg) + R2. The median age was 65 y (range, 30-79), 58% of patients had stage IV disease, 52% had FLIPI 3-5, 31% had primary refractory disease, and 47% had experienced disease progression within 24 mo after starting first-line treatment. Half of patients (50%) had received 1 prior line of therapy (range, 1-9). Treatment was ongoing in 56 patients (90%), with a median follow-up of 4.0 mo. Six patients discontinued therapy due to disease progression (n=4) or other reasons (death due to COVID-19, n=1; reason unknown, n=1). The most common treatment-emergent AEs of any grade were CRS (37%; 27% grade 1, 10% grade 2, no grade 3-4), neutropenia (29%; 5% grade 1-2, 24% grade 3-4), fatigue (26%; 24% grade 1-2, 2% grade 3-4), and injection-site reactions (26%; all grade 1-2). Most CRS events (in 35% of all evaluable patients) occurred after the first full dose of epcoritamab. All CRS events resolved (median time to resolution, 2 d; range, 1-4), no patients discontinued treatment due to CRS, and 5 patients received tocilizumab. ICANS (grade 1) occurred in 1 patient 22 d from the start of treatment, and it resolved in 7 d. There were no clinical tumor lysis syndrome events. Among 41 efficacy-evaluable patients, the overall response rate was 95% (39/41), with 73% of patients (30/41) achieving a complete metabolic response (CMR) as their best overall response. Most CMRs (27/30) were achieved by the first assessment (6 wk), and nearly all (29/30) were ongoing at the time of data cutoff. Of the 9 patients with a partial metabolic response, 6 had an ongoing response at the time of data cutoff. The longest duration of response was 4.5+ mo. Median progression-free survival was not reached (Figure). Conclusions: In patients with R/R FL, subcutaneous epcoritamab + R2 demonstrated a manageable safety profile with only low-grade CRS events, mostly observed following the first full dose and all of which resolved. No new safety signals were detected. Data from this cohort are very encouraging with a high CMR rate observed in patients with R/R FL. These data are consistent with prior results from the EPCORE NHL-2 trial and supportive of ongoing investigation of epcoritamab + R2 in patients with R/R FL. A phase 3 trial of epcoritamab + R2 compared with R2 alone in patients with R/R FL (EPCORE FL-1) will open in 2022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal