Epcoritamab plus R-DHAX/C (rituximab [Rituxan], dexamethasone, cytarabine, and oxaliplatin/carboplatin) displayed encouraging responses in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are eligible for autologous stem cell transplant (ASCT), according to preliminary results from arm 4 of the phase 1b/2 EPCORE NHL-2 trial (NCT04663347), which were presented at the 2022 EHA Congress.

The overall response rate (ORR) in this arm was 88%, with 65% achieving complete metabolic response (CMR; n = 17). Specifically, 100% of patients who received transplant responded (n = 14), with 86% achieving CMR (n = 12). Additionally, 75% of patients who did not receive transplant responded (n = 9), with 42% achieving CMR (n = 5).

“We have a second attempt to cure these patients when we offer second-line chemotherapy plus ASCT,” said lead study author Raul Córdoba, MD, PhD, coordinator of the Lymphoma Unit at University Hospital Fundación Jiménez Díaz. “We need to improve the efficacy data of the strategy that we are using in order to proceed to ASCT, using platinum-based regimens such as R-DHAX/C.”

The current standard of care for relapsed/refractory DLBCL is salvage chemoimmunotherapy, such as R-DHAX/C followed by consolidation with high-dose therapy (HDT) and ASCT. However, responses to salvage therapy are often poor, which leaves patients ineligible for ASCT or with a poor prognosis after receiving ASCT.

Epcoritamab is a bispecific antibody administered subcutaneously that simultaneously binds to CD20 on B cells and CD3 on T cells, inducing T-cell–mediated killing of CD20-positive malignant B cells. This mechanism of action, which is distinct from salvage chemoimmunotherapy with R-DHAX/C, makes the agent an optimal combination partner. In the dose-escalation part of the phase 1/2 EPCORE NHL-1 trial (NCT03625037), epcoritamab monotherapy showed meaningful antitumor activity and manageable toxicity in patients with heavily pretreated B-cell non-Hodgkin lymphoma (NHL).

The EPCORE NHL-2 trial is an open-label, multicenter trial investigating the antitumor activity and safety of epcoritamab plus standard-of-care R-DHAX/C in patients with high-risk B-cell NHL. Specifically, arm 4 evaluated epcoritamab plus R-DHAX/C in adult patients with relapsed/refractory DLBCL who were eligible for HDT and ASCT.

Eligible patients included those with relapsed/refractory, de novo or histologically transformed CD20-positive DLBCL, including T-cell/histocyte­–rich DLBCL, double-hit or triple-hit DLBCL, and grade 3B follicular lymphoma. Patients also needed to be eligible for R-DHAX/C and HDT and ASCT (HDT-ASCT), with an EGOG performance status of 0 to 2. Additional eligibility criteria included adequate organ function and disease measurable by magnetic resonance imaging or computed tomography (CT).

The median age of patients enrolled in the trial was 58 years (range, 28-75 years). Of these patients, 72% had received 1 prior line of therapy (n = 21), 21% had received 2 prior lines (n = 6), 7% had received 3 prior lines (n = 2), and 10% had received previous CAR T-cell therapy (n = 3). In total, 66% of patients had primary refractory disease (n = 19), and 48% relapsed within 6 months after therapy (n = 14). A total of 59% of patients (n = 17) were refractory to their last line of therapy.

The median time from the end of a patient’s previous line of therapy to their first dose of epcoritamab plus R-DHAX/C was 6 months (range, 1-49).

A total of 29 patients received the combination every week for 3, 21-day cycles.

Rituximab was administered intravenously (IV) at a dose of 375 mg/m

 every 3 weeks, dexamethasone at 40 mg/d IV or orally on days 1 through 4, cytarabine at 2 g/m

 IV repeated after 12 hours every 3 weeks, carboplatin at an area under the curve of 5 mg/mL x min (Calvert formula) or oxaliplatin at 100 mg/m

 IV every 3 weeks. Patients who had postponed HDT-ASCT could continue with 28-day cycles of epcoritamab monotherapy weekly in cycle 4, every 2 weeks in cycles 5 through 9, and every 4 weeks thereafter until progressive disease (PD) or unacceptable toxicity. Responses were assessed by positron emission tomography-CT using Lugano 2014 criteria. Step-up subcutaneous epcoritamab dosing and corticosteroid prophylaxis were required in cycle 1 to mitigate cytokine release syndrome (CRS).

At a data cutoff of March 25, 2022, and a median follow-up of 5.8 months (range, 1.5-11.4), 52% of patients received transplant after epcoritamab treatment (n = 15). Of the 48% of patients who did not receive transplant (n = 14), 21% received ongoing treatment (n = 6), 21% discontinued treatment due to PD, and 7% discontinued treatment due to adverse effects (AEs; n = 2).

Additional results indicated that of the 14 patients who received ASCT, 14% (n = 2) achieved partial metabolic response (PMR). A total of 12 patients postponed or canceled HDT-ASCT and continued epcoritamab monotherapy. Of these patients, 33% achieved PMR (n = 4). Of the entire evaluable population (n = 26), 23% achieved PMR (n = 6). A total of 2 patients who did not receive ASCT experienced PD compared with no patients who received ASCT.

Epcoritamab plus R-DHAX/C had a manageable safety profile, and no new safety data were observed. All CRS events were low grade and resolved with standard management. There was 1 grade 2 immune effector cell–associated neurotoxicity syndrome (ICANS) event that resolved.

The most common treatment-emergent AEs (TRAEs) of any grade were thrombocytopenia (65%), neutropenia (44%), nausea (38%), CRS (38%), and anemia (38%). AEs of special interest included grade 1 or 2 CRS, which resolved in a median time of 2 days, and grade 2 ICANS, which occurred in 1 patient who had received prior CAR T-cell therapy. In total, 2 patients had TEAEs that led to epcoritamab discontinuation: 1 with grade 2 ICANS and 1 with Guillain-Barré syndrome. No clinical tumor lysis syndrome was reported. No fatal TEAEs were observed. AEs were graded by the Common Terminology Criteria for Adverse Events version 5.0 criteria.

In total, 38% of all patients experienced CRS (n = 11), with 28% experiencing grade 1 CRS (n = 8) and 10% experiencing grade 2 CRS (n = 3).

“We have seen very encouraging high response rates, so we can increase the number of patients who can proceed to ASCT and offer a [therapy with] curative intention,” Córdoba concluded.

These findings support further investigation of epcoritamab plus R-DHAX/C in transplant-eligible patients with relapsed/refractory DLBCL.

Córdoba R, Falchi L, Phillips T, et al. Preliminary phase 1/2 results of subcutaneous epcoritamab + R-DHAX/C in patients with relapsed or refractory diffuse large B-cell lymphoma eligible for autologous stem cell transplant. Presented at: EHA 2022 Hybrid Congress; June 9-12, 2022; Vienna, Austria. Abstract P1215

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Epcoritamab plus rituximab, dexamethasone, cytarabine, and oxaliplatin or carboplatin displayed encouraging responses in patients with relapsed/refractory diffuse large B-cell lymphoma who are eligible for autologous stem cell transplant, according to preliminary results from arm 4 of the phase 1b/2 EPCORE NHL-2 trial.

Epcoritamab Plus R-DHAX/C Demonstrates High Response Rates and Manageable Safety in DLBCL

CT041, a Claudin18.2 (CLDN18.2)–specific CAR T-cell therapy, demonstrated a manageable safety profile in patients with previously treated, CLDN18.2-positive advanced gastric/gastroesophageal junction (gastric/GEJ) cancer, with a majority of patients achieving partial response or stable disease, according to findings from a phase 1b study (NCT04404595) that were presented at the 2022 ASCO Annual Meeting.

In the single-arm study, the objective response rate (ORR) with CT041 was 33% across efficacy evaluable patients enrolled in the study (n = 12), which included 1 complete response in a patient with metastatic gastric cancer. When including stable disease, disease control was observed in two-thirds of patients. There were no dose-limiting toxicities observed and no cases of grade 3 or greater cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), gastrointestinal bleeding, or acute gastric mucosal injury.

“Even in patients who have been through 4 or more lines of chemotherapy, CLDN18.2 CAR-T cells produced dramatic and even complete responses,” said lead author Gregory P. Botta, MD, PhD, medical oncologist and associate professor of medicine at the Moores Cancer Center of UC San Diego Health. “Importantly, many responses were durable for months, allowing patients to improve performance status and quality of life. These early responses provide a signal to move into larger prospective trials of CT041 CAR T-cell therapy in solid tumors expressing CLDN18.2.”

Findings from the study, which was conducted in the United States, align with results from a phase 1b/2 study completed in China of CT041 in patients with gastric and gastroesophageal junction adenocarcinoma. Updated findings from this study were also presented at the 2022 ASCO Annual Meeting showing an ORR of 57.1% in 13 evaluable patients. This included all partial responses. When including stable disease, the DCR was 78.6%. The median progression-free survival was 5.6 months and the median overall survival was 10.8 months.

CLDN18.2 is highly expressed in the gastric mucosa and intestinal epithelium and has been found to be highly expressed across a variety of cancers, especially those in the gastrointestinal tract. This high level of expression in malignant cells indicates it as an ideal candidate for targeted therapies.

 CT041 consists of an anti-CLDN18.2 scFv with a CD28 costimulatory domain and a CD3ζ signaling domain, which are linked with a CD8α hinge region and CD28 transmembrane region.

In the phase 1b study,1 14 patients were enrolled at 6 centers across the United States: 5 patients with gastric cancer and 9 with pancreatic adenocarcinoma. All patients were positive for CLDN18.2 expression. Patients had received a median of 3 prior lines of therapy (range, 1-5) before entering the study.

“Diffuse signet-ring gastric adenocarcinoma and pancreatic ductal adenocarcinoma have few effective options for treatment aside from traditional chemotherapy,” said Botta. “Unfortunately, chemotherapy responses and side effects restrict prolonged treatment.”

Once enrolled, patients underwent leukapheresis for cell therapy manufacturing. Prior to CT041 CAR T-cell infusion, a conditioning regimen of fludarabine, cyclophosphamide, and nab-paclitaxel (Abraxane) was administered. Three dose levels (DL) of CT041 were analyzed in the study. DL1 was 2.5 to 3.0 × 10

 cells (n = 6), DL2 consisted of 3.75 to 4.0 × 10

 cells (n = 2). At the time of the assessment, efficacy data were available only for DL1 and DL2.

In the DL1 group, 1 of 6 patients experienced a response (16.7%) with 2 additional patients having stable disease, for a DCR of 50%. A higher response rate was seen in the DL2 group, with 2 of 6 patients having a response (33.3%) and 3 experiencing stable disease, for a DCR of 83.3%. Across all patients who experienced stable disease (n = 5), 80% had some level of tumor shrinkage that did not meet criteria for a partial response (30%).

In those with gastric cancer (n = 5), the ORR was 60% and there was 1 patient with stable disease (DCR, 80%). In those with pancreatic cancer (n = 7), there were no responses and 4 cases of stable disease (57.1%), all demonstrating some level of tumor shrinkage. The median duration of response and progression-free survival were not yet met.

Low-grade CRS was observed in 93% of patients following CT041 infusion, with 11 patients (79%) having a grade 1 event and 2 (14%) having a grade 2 event. The median time to onset of CRS was 2 days (range, 1-3) and only 2 patients required intervention with tocilizumab for grade 2 CRS. The median duration of CRS was 2 days (range, 1-8).

“Solid tumors, including gastric cancer, are of high incidence globally. As treatment options for gastric cancer are still limited, there is a strong need for more innovative therapies,” Raffaele Baffa, MD, PhD, chief medical officer of CARsgen Therapeutics Holdings Limited, the company developing CT041, said in a statement. “The updated clinical data of CT041 at ASCO 2022 are very encouraging in pre-treated GC/GEJ and GC patients, demonstrating significant efficacy and excellent tolerability, including the impressive ORR of 60% and a case of CR. We look forward to the continuing development of CT041 and we believe it can help more patients.”

The phase 1b study is continuing to enroll participants in the dose-escalation portion of the trial. Once a dose is identified, an expansion cohort will open to further evaluate the cell therapy at this dose level. Overall, the study anticipates enrolling 110 total participants and expects to complete in June 2025.

Botta GP, Becerra CR, Jin Z, et al. Multicenter phase Ib trial in the U.S. of salvage CT041 CLDN18.2-specific chimeric antigen receptor T-cell therapy for patients with advanced gastric and pancreatic adenocarcinoma. 

. 2022;40(suppl 16):2538. DOI:10.1200/JCO.2022.40.16_suppl.2538

Qi C, Liu C, Gong J, et al. Safety, tolerability, and preliminary efficacy results in patients with advanced gastric/gastroesophageal junction adenocarcinoma from a phase Ib/II study of CLDN18.2 CAR T-cell therapy (CT041). 

. 2022;40(suppl 16):4017. DOI: 10.1200/JCO.2022.40.16_suppl.4017

Sahin U, Koslowski M, Dhaene K, et al. Claudin-18 Splice Variant 2 Is a Pan-Cancer Target Suitable for Therapeutic Antibody Development. 

. 2008;14 (23):7624-7634. DOI: 10.1158/1078-0432.CCR-08-1547

CT041, a Claudin18.2–specific CAR T-cell therapy, demonstrated a manageable safety profile in patients with previously treated, CLDN18.2-positive advanced gastric/gastroesophageal junction cancer, with a majority of patients achieving partial response or stable disease.

CT041 CAR T-cell Therapy Elicits Manageable Toxicity and Durable Response in Gastric/GEJ Cancer

BTX-1188, a first-in-class oral molecular glue, is currently undergoing investigation in phase 1 clinical trials in patients with solid tumors or acute myeloid leukemia (AML), after preclinical trials supported its potential safety benefits in this population and demonstrated its high sensitivity in Myc-driven cancer cell lines, according to findings from a poster presented at the 2022 ASCO Annual Meeting.

BTX-1188 could prevent systemic inflammatory dose-limiting toxicities that are usually attributed to pure GSPT1 (G1 to S phase transition 1) degradation due to its immunomodulatory properties from the IKZF1/3 (Ikaros/Aiolos) degradation. The FDA granted an investigational new drug application for BTX-1188 and a phase 1 trial (NCT05144334) was initiated to assess the safety and toxicity profile, as well as the pharmacokinetics and preliminary activity, of the drug in hematologic and solid malignancies.

The translation termination factor GSPT1 and transcription factor IKZF1/3 are required for the development and differentiation of lymphocytes and the modulation of cytokines.1 “BTX-1188…degrades GSPT1 and Ikaros/Aiolos, or IKZF1 and IKZF3, thereby resulting in inhibition of protein translation and in modulation of cytokines, respectively,” Aparajita Hoskote Chourasia, PhD, said in her presentation.

For the preclinical study, investigators gave athymic or BALB/c nude mice xenograft models a vehicle or BTX-118. They measured cell viability in cells treated with BTX-118 and patient samples by CellTiter-Glo 2.0 assay. Immunoblots of protein lysates from cells treated with DMSO (dimethyl sulfoxide) or BTX-118 were used to analyze substrate degradation and apoptosis profiles. Interleukin (IL)-2 or lipopolysaccharide (LPS)-induced measurements of inflammatory cytokines upon DMSO or compound treatment were taken after human peripheral blood mononuclear cells (PBMCs) were stimulated with αCD3.

In addition to rapid and deep degradation of GSPT1 and IKZF1/3, BTX-1188 is also an inhibitor of Myc in multiple cell lines. The AML cell line MV-4-11 showed significant GSPT1 and IKZF1/3 degradation after 2 hours of treatment with 100 nM of BTX-1188 (

< 1 × 10-5) and 6 hours with 3 nM (>90% of GSPT1), respectively, in a proteomics and immunoblot analysis.

According to the study investigators, this indicates rapid and potent neosubstrate degradation.

“Our data show that it has single-digit nanomolar DC50 for the Cereblon neosubstrates both in AML and in lymphoma, and that it also significantly inhibits Myc at low nanomolar concentrations,” Chourasia explained.

The investigators also observed significantly lower levels of GSPT1 and sustained apoptosis after treatment with 30 nM for 6 hours followed by washout, similar to what has been seen with PARP cleavage for up to 24 hours. BTX-1188’s durability in degrading GSPT1 expresses as low nanomolar IC50 even though there was 72-hour period of compound washout.

Inhibition of proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor α, and induction of IL-2 by LPS and αCD3-stimulated peripheral blood mononuclear cells demonstrates BTX-1188 immunomodulatory properties. “These immunomodulatory properties are expected to improve clinical outcomes and reduce toxicities associated with selective GSPT1 degradation [without IKZF1/3 degradation], thus expanding its therapeutic window,” Chourasia said.

For cancer cell lines such as primary human patient AML samples (IC50 range, 0.4-1.5 nM) and Myc-dependent and non-Myc dependent lines (IC50 range, 0.5-20 nM), BTX-1188 is functionally cytotoxic. This includes samples from disease that is relapsed/refractory, cytarabine resistant, or venetoclax (Venclexta) resistant.

In vivoefficacy models which received daily or intermittent dosing of BTX-1188 also showed durability of GSPT1 degradation and sustained apoptosis, further indicating significant and sustained antitumor activity.

“Based on this data, our drug has entered phase 1 clinical studies for both solid tumors, as well as AML,” Chourasia concluded.

The sequential dose-escalation study currently enrolling patients to investigate BTX-1188 is multicenter, open label, and nonrandomized. The approximately 168 eligible patients with AML, advanced solid tumors, or non-Hodgkin lymphoma will receive 1 of 7 doses of BTX-1188. Evaluation of treatment-emergent adverse effects and determination of the recommended phase 2 dose are the primary end points of the trial.

Chourasia AH, Majeski H, Pasis A, et al. BTX-1188, a first-in-class dual degrader of GSPT1 and IKZF1/3, for treatment of acute myeloid leukemia (AML) and solid tumors. 

BioTheryX receives IND clearance from FDA to proceed with phase 1 study of BTX-1188, a molecular glue, for the treatment of hematologic and solid malignancies. News release. PRNewswire. Published November 2, 2021. Accessed June 3, 2022. 

BTX-1188, a first-in-class oral molecular glue, is undergoing investigation in phase 1 clinical trials in patients with solid tumors or acute myeloid leukemia, after preclinical trials supported its potential safety benefits in this population and demonstrated its high sensitivity in Myc-driven cancer cell lines.

Pipeline Report: June 2022

Articles

Epcoritamab Plus R-DHAX/C Demonstrates High Response Rates and Manageable Safety in DLBCL

CT041 CAR T-cell Therapy Elicits Manageable Toxicity and Durable Response in Gastric/GEJ Cancer