Prior Lines Of Tx Research Articles

Subcutaneous epcoritamab + GemOx in patients with relapsed or refractory DLBCL: Updated results from EPCORE NHL-2.

7037 Background: Gemcitabine + oxaliplatin (GemOx) is commonly used with rituximab to treat relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL); however, outcomes are suboptimal: 33% complete response (CR) rate; 5 mo median progression-free survival (PFS); 10 mo median overall survival (OS; Cazelles et al, Leuk Lymphoma 2021). We report additional efficacy and safety results of epcoritamab + GemOx in difficult-to-treat R/R DLBCL (EPCORE™ NHL-2 phase 1/2 trial, NCT04663347). Methods: Adults with R/R CD20+ DLBCL who failed or were ineligible for autologous stem cell transplant (ASCT) enrolled to receive subcutaneous (SC) epcoritamab (2 step-up doses followed by 48-mg full doses) in 28-d cycles (C): QW, C1–3; Q2W, C4–9; Q4W, C≥10 until unacceptable toxicity or disease progression. GemOx was given Q2W in C1–4. The primary endpoint was overall response rate (ORR) per Lugano criteria. Subgroup analyses by prior treatment (tx) and response were performed. Results: As of Sept 1, 2023, 97 pts with ≥6 mo of follow-up had received epcoritamab 48 mg + GemOx (median follow-up, 9.7 mo). Pts had a median of 2 prior lines of tx (pLOT; range, 1–6); 55% had primary refractory disease, 38% had bulky disease (>6 cm), 30% had prior CAR T, and 9% had prior ASCT. Median age was 72 y, with 34% of pts ≥75 y. A median of 7 cycles of epcoritamab and 4 cycles of GemOx were initiated. At data cutoff, tx was ongoing in 46% of pts. ORR was 78% and CR rate was 55%. Median time to CR was 1.7 mo; median duration of CR was 13.3 mo. Additional efficacy outcomes are shown in the Table. Safety was consistent with previous reports. The most common tx-emergent AEs (TEAEs) of any grade (G) were hematologic AEs (68% thrombocytopenia; 59% neutropenia [6% febrile neutropenia]; 51% anemia) and CRS (51%). CRS was primarily low grade (27% G1, 23% G2), with only 1 pt experiencing G3 CRS; all events resolved and none led to tx discontinuation. ICANS was reported in 3 pts (G1, n=2; G3, n=1); all events resolved, but 1 pt discontinued tx. There were 13 fatal TEAEs; in 3 cases, the contribution of epcoritamab + GemOx could not be ruled out: COVID-19, multiple organ dysfunction syndrome, and small intestinal perforation. Conclusions: These long-term results continue to demonstrate that SC epcoritamab in combination with GemOx leads to deep, durable responses, which translate to high rates of PFS and OS in challenging-to-treat, high-risk pts with R/R DLBCL. CR rates were consistently high across prespecified subgroups. Higher CR rates in pts with 1 vs ≥2 pLOT indicate that earlier use may further improve outcomes. No new safety signals were identified. The benefit-risk profile of this combination supports the combinability of epcoritamab in R/R DLBCL. Clinical trial information: NCT04663347 . [Table: see text]

A phase 2, multicenter, open-label, dose-optimization study evaluating telomere-targeting agent THIO sequenced with cemiplimab in patients with advanced NSCLC: Updated results.

8601 Background: Despite recent approvals for the first-line (1L) treatment of advanced non-small-cell lung cancer (NSCLC), long-term prognosis remains poor with a 5-year survival rate of 28% and limited options exist in patients (pts) refractory or resistant to immune checkpoint inhibitors (ICI). THIO (6-thio-2’-deoxyguanosine) is a small molecule, first-in-class direct cancer telomere-targeting agent that selectively targets telomerase positive (TERT+) cancer cells. It is incorporated de novo in synthesized telomeres leading to chromatin uncapping, generation of DNA damage signals, and rapid apoptosis. In advanced cancer animal models, THIO followed by an ICI demonstrated the ability to overcome ICI resistance. Methods: Here we describe a phase 2 dose-optimization study (NCT05208944) for adults with advanced NSCLC who progressed or relapsed after 1–4 prior treatment (tx) lines including 1L ICI alone or in combination with platinum chemotherapy. Following a safety lead-in of 10 pts who received THIO 360 mg IV [120 mg QD, D1–3] followed by 350 mg IV cemiplimab on D5 Q3W, the study proceeded to a 2-stage design with pts randomized to 1 of 3 arms: THIO 60 mg, 180 mg, or 360 mg, all followed by cemiplimab Q3W. In Stage 1 if at least 8 of 19 pts/arm achieved disease control, an additional 22 pts could be enrolled in that arm (up to 41 pts/arm). Study endpoints include safety (DLTs and AEs/SAEs) and efficacy (ORR, DCR, DOR, PFS, and OS). Results: Recruitment into the 360 mg arm was paused after 4 pts following 1 instance of G4 ALT Increase and AST Increase (without clinical presentation). At the end of Stage 1 cut-off (13-Nov-2023), the DCR greatly exceeded the threshold required for Stage 2 expansion in both arms: 60 mg 14/16 (88%); 180 mg 11/13 (85%). The 180 mg dose was selected for further investigation by the trial’s Safety Review Committee based on superior efficacy (31% PR rate; 54% reduction in tumor burden). As of 8-Jan-2024, 56 pts received ≥1 dose of THIO in the 60 and 180 mg arms (24 and 32 pts, respectively). Prior lines of tx at study entry were: 60 mg (1L 75%, 2L 21%, 3L 4%); 180 mg (1L 66%, 2L 31%, 4L 3%). Most pts received platinum chemotherapy prior to study entry (60 mg 88%; 180 mg 78%). Across all pts treated n=70, most AEs were G1/2. The most frequent related AEs were AST increase (23%), ALT increase (20%), and nausea (11%). All instances of LFT elevations were without clinical symptoms and resolved to baseline. Conclusions: THIOfollowed by cemiplimab was generally well tolerated in this difficult-to-treat population (all pts progressing following ICI tx and the majority following platinum chemotherapy). Based on safety and promising efficacy, the 180 mg dose was selected for further development. Enrollment is ongoing and is expected to be completed in Feb-2024. Updated primary endpoint data, including preliminary durability data, will be presented. Clinical trial information: NCT05208944 .

9MW2821, a nectin-4 antibody-drug conjugate (ADC), in patients with advanced solid tumor: Results from a phase 1/2a study.

3013 Background: 9MW2821 is a monoclonal ADC that delivers monomethyl auristatin E to cells expressing Nectin-4. Nectin-4 is an adhesion molecule that highly expressed in variety of solid tumors, especially urothelial cancer (UC), cervical cancer (CC), esophageal cancer (EC) and breast cancer. Here we report the updated safety and efficacy data of 9MW2821. Methods: 9MW2821 was administered by intravenous infusion at doses of 0.33-1.5mg/kg on days 1, 8 and 15 of each 28-day cycle. The study included dose escalation, dose expansion and cohort expansion period which included UC, CC, EC, triple negative breast cancer (TNBC) and other Nectin-4 positive solid tumors that progressed after ≥1 systemic treatments (Tx). Primary objectives were assessment of safety and preliminary efficacy. Results: As of Jan 15, 2024, 260 patients (pts) were enrolled with doses ranging from 0.33 to 1.5mg/kg. Only 1 out of 6 pts in 1.5mg/kg group had dose limiting toxicity (grade 4 neutropenia lasted more than 5 days). The maximum tolerated dose was not reached up to 1.5mg/kg and the RP2D was selected as 1.25mg/kg for tolerance. 240 pts were enrolled at dose of 1.25mg/kg. The most common TRAEs of 1.25mg/kg dose group (≥20%, all grade/≥5%, ≥G3) were white blood cell (WBC) count decreased (50.8%, 23.3%), neutrophil count decreased (46.3%, 27.9%), anemia (43.8%, 8.3%), aspartate aminotransferase increased (42.1%, 2.9%), alanine aminotransferase increased (35.4%, 2.1%), asthenia (32.1%, 2.9%), rash (30.0%, 5.0%), decreased appetite (28.8%, 1.3%), nausea (26.7%, 0%), hyperglycemia (25.4%, 2.1%), platelet count decreased (24.2%, 4.6%), alopecia (24.2%, 0%), hypoaesthesia (22.5%, 1.7%), constipation (21.3%, 0%), vomiting (20.9%, 1.3%), hypertriglyceridemia (20.4%, 2.1%), gamma-glutamyltransferase increased (15.8%, 5.4%). Among 190 pts treated with 9MW2821 at 1.25mg/kg or above and reached tumor assessment, objective response rate (ORR) and disease control rate (DCR) was 35.3% and 78.4%, respectively. 37 UC pts, 45 CC pts, 27 EC pts and 16 TNBC pts were enrolled at 1.25mg/kg and evaluable for tumor assessment. Median prior lines of Tx were 2 (range, 1-4). All UC, 51% CC and 93% EC pts progressed after platinum-based chemotherapy and immune checkpoint inhibitors, respectively. Objective responses were also observed in pts with other solid tumor types. Conclusions: The data indicated encouraging efficacy of 9MW2821 in advanced UC, CC, EC and TNBC. 9MW2821 is the first Nectin-4 targeting ADC showed antitumor activity in patients with CC, EC and TNBC. The safety profile showed adequate tolerability. Clinical trial information: NCT05216965 . [Table: see text]

Health-related quality of life (HRQoL), functioning, and symptoms with odronextamab monotherapy in patients (pts) with relapsed or refractory follicular lymphoma (R/R FL) by POD24 status in the ELM-2 study.

e19057 Background: In ELM-2 (NCT03888105), a Ph 2, single arm, open label trial, odronextamab demonstrated robust efficacy, generally manageable safety, and overall maintenance of patient-reported outcomes (PROs) in R/R FL pts (Villasboas et al. ASH 2023). In FL, pts with disease progression within 2 yrs of frontline chemoimmunotherapy (POD24) are hard to treat with poor clinical outcomes, representing an unmet need. We report PROs by POD24 status in pts with Grade 1–3a R/R FL from ELM-2. Methods: Pts received IV odronextamab in 21-day cycles (C): 80 mg QW in C1–4, with C1 dose step up to mitigate cytokine release syndrome, then 160 mg Q2W (Q4W if complete response ≥9 mo) until progression. PROs were collected at baseline (BL), Wks 2–4, 10, then Q8W in Yr 1, and Q12W in Yr 2. Post-hoc POD24 subgroup analyses were performed on six EORTC QLQ-C30 scales, the EQ-5D-3L VAS, and FACT-Lym LymS. Estimated mean change from BL (CFB) was analyzed using mixed models for repeated measures (MMRM) through Wk 42 (≥10 pts at last assessment). Published meaningful CFB thresholds were used to define deterioration/improvement in responder analyses. Results: By Jan 31, 2023, 140 pts with R/R FL had received odronextamab. Pts with POD24 (n=70) were younger than pts without POD24 (n=70; median age 57.5 vs 62.0 y), had fewer prior Tx lines (median 2 vs 3), and a higher proportion double refractory to anti-CD20 Ab + alkylator (53% vs 29%). Objective response rate was similar in evaluable pts with (n=63; 79%) and without (n=65; 80%) POD24. PRO questionnaire completion ranged from 52–95% through Wk 42 across groups. Descriptive analyses suggest BL PRO scores were similar by POD24 status, showing good HRQoL/functioning and low symptom burden, and were generally maintained through Wk 42 with minimal between-group differences (overlapping 95% CIs for LS mean CFB [Table]). In both groups, more pts reported PRO maintenance or improvement vs deterioration across visits, except for fatigue at Wk 10 in pts without POD24. Conclusions: In pts with heavily pretreated R/R FL, odronextamab Tx maintained HRQoL, functioning, and symptoms irrespective of POD24 status. Clinical trial information: NCT03888105 . [Table: see text]

Real-world treatment (Tx) sequences and time to discontinuation (rwTTD) in the first-line (1L) metastatic castration-resistant prostate cancer (mCRPC) setting.

55 Background: There is limited real-world data on tx sequencing in metastatic prostate cancer. Additionally, while guidelines support adding novel hormonal agents (NHA) to androgen deprivation tx (ADT) for metastatic hormone-sensitive prostate cancer, use is limited because of clinical and/or pt-driven factors. We evaluated tx patterns, rwTTD, and time-to-chemotherapy (rwTTC) for 1L mCRPC pts, including Black/African Americans (BAA) treated predominantly in a community oncology setting. Additionally, we analyzed systemic treatments prior to 1L mCRPC as well as progression to 2L mCRPC. Methods: This retrospective study included pts with mCRPC from the nationwide Flatiron Health EHR-derived, deidentified database who initiated 1L tx between 1/2013 and 1/2023. Study end was 4/2023. Tx patterns were described by time period (TP) of 1L initiation: TP1 - 01/2013–12/2017 and TP2 - 01/2018–01/2023; Kaplan-Meier analyses were conducted for rwTTD/TTC and a Cox proportional hazards regression model was used to determine the association between pt characteristics and rwTTD/TTC for 1L mCRPC. Subgroup analyses were performed for BAAs. Results: Of the 8915 1L-tx pts (median age 74 yrs), 871 (10%) were BAA (median age 70 yrs) and 5870 (66%) were NHA-naïve at 1L mCRPC. Overall, the percent of pts who were NHA-naïve decreased from 2018 (72%) to 2023 (39%) and a similar trend was observed for BAA (74% [2018] to 25% [2023]). 1L NHA use in mCRPC increased from TP1 to TP2 (overall: 70% to 80%; BAA: 73% to 83%), primarily driven by enzalutamide (Enz) (overall: 30% to 39%; BAA: 33% to 38%) and decrease in chemotherapy (overall: 16% to 12%; BAA: 17% to 13%). The top 3 1L mCRPC regimens for the overall population and BAA were abiraterone (Abi) (35%; 38%), Enz (32%; 33%), and docetaxel (10%; 11%). Among pts who progressed to 2L mCRPC, the most common sequences for patients tx with Abi or Enz for 1L mCRPC were ADT monotherapy in the prior line of tx and a switch to Abi (19%) or Enz (24%) upon progression from 1L to 2L. 1L rwTTD for the overall cohort is in the Table. Age ≥80 years, ECOG PS ≥1, socioeconomic status = 5 (highest), and median time ≤39.8 months from initial dx to mCRPC were associated with a higher hazard of discontinuation (all p ≤0.05). Conclusions: Overall, most pts received their first NHA in 1L mCRPC; NHA use increased and chemotherapy use decreased from TP1 to TP2. There was heterogeneity in tx sequences in patients treated with an NHA in 1L mCRPC; some pts were rechallenged with a different NHA in 2L despite lack of robust prospective data to support use. Overall, 1L rwTTD was short with a small numerical increase in TP2. Factors contributing to discontinuation, such as treatment resistance, need to be better understood to further improve real-world outcomes. [Table: see text]

Results of the safety and tolerability of ivaltinostat plus capecitabine in the phase 1b portion of a phase 1b/2, dose-escalation, randomized, multi-center study in the maintenance (maint) setting in patients with metastatic pancreatic adenocarcinoma (mPDAC).

666 Background: The standard of care for patient (pts) with advanced or mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel used in the front-line setting until disease progression (prog) or toxicity. A tolerable maint therapy (tx) that can effectively delay disease prog while preserving quality of life with minimal cumulative toxicity is highly desirable. There is no standard main tx. Ivaltinostat (ival) is a pan-HDAC (histone deacetylation) inhibitor that increases histone acetylation (HA), suppresses PDAC cell proliferation, and promotes apoptosis in PDAC cell lines. Preclinical data demonstrated synergy with 5-FU/capecitabine in mouse models. The phase 1b study will determine an optimal combination of ival and cape followed by a randomized P2 trial of ival plus cape vs cape alone in the maint setting for pts with mPDAC who have not progressed on front-line mFOLFIRINOX. Methods: Key eligibility criteria for P1b include: locally advanced or mPDAC; at least 1 prior line of tx regardless disease prog; ECOG PS 0-1; and no known gBRCA1/2 mutation. Dose-limiting toxicities (DLT) in 3 dose levels of ival, (60, 125, and 250mg/m2 iv weekly on days 1 and 8) in combination with cape (1000mg/m2 po BID on days 1-14) of a 21-day cycle will be evaluated. The primary objective is to evaluate the safety, tolerability and determine the recommended phase 2 dose (RP2D) as well as pharmacokinetics (PK) of ival and cape. Results: As of the date of data-cut, 32 pts had been enrolled at the 60 (7 pts), 125 (14 pts) and 250 (11 pts) mg/m2 dose level, 8 were screen failures and 9 still ongoing with a goal of at least 6 DLT-evaluable pts per dose level. Average prior lines of tx was 3.6 (range 1-5). The median age was 68 (range 51-83) and 21(66%) were males. No DLTs were observed across the 3 dose levels. SAEs occurred in 2 pts that were not related to study drugs. Both ival and cape-related TEAEs were similar except palmar-plantar erythrodysesthesia syndrome (PPES) 9(28%) attributed to cape; fatigue, diarrhea and nausea were the only TEAEs occurred >15%. Two pts had ³grade 3 diarrhea, another pt had cape-related PPES. The TEAE profile was similar across the dose levels. At the time of data-cut there were 6 deaths among pts who discontinued study due to prog. Among 15 pts who had been evaluated for response since baseline, the best ORR were 11 SD(73.3%), 1(6.7%) no RECIST-measurable evidence of disease and 3 PD(20%). PK evaluations for ival indicated dose proportionate increases. The trend of PK observed in this study was similar to the PK trend observed in previous studies. Conclusions: Combination therapy of ival with cape has been well tolerated and the safety and PK/PD data support a RP2D of ival of 250 mg/m2. Clinical trial information: NCT05249101 .

Outcomes of Patients with Relapsed/Refractory Lymphoplasmacytic Lymphoma Treated with Venetoclax: A Multicenter Retrospective Analysis

Outcomes of Patients with Relapsed/Refractory Lymphoplasmacytic Lymphoma Treated with Venetoclax: A Multicenter Retrospective Analysis

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.

Phase 3 THOR study: Results of erdafitinib (erda) versus chemotherapy (chemo) in patients (pts) with advanced or metastatic urothelial cancer (mUC) with select fibroblast growth factor receptor alterations (FGFRalt).

LBA4619 Background: FGFRalt are observed in ~20% of pts with mUC. Erda is an oral selective pan-FGFR tyrosine kinase inhibitor granted accelerated approval to treat locally advanced or mUC in adults with susceptible FGFR3/2alt who have progressed after platinum-containing chemo. THOR (NCT03390504), a randomized phase 3 study, assessed whether erda provided a survival advantage vs investigator’s choice of chemo in pts with mUC who progressed after 1 or 2 prior treatments, including an anti-PD-(L)1 agent. Methods: Pts (≥18 y) with unresectable advanced/mUC and select FGFR3/2alt (mutations/fusions), ECOG performance status 0-2, adequate organ function, progression on/after prior systemic therapy (tx) that included an anti-PD-(L)1 agent, and ≤2 prior lines of tx were randomized 1:1 to receive erda (8 mg with pharmacodynamically guided uptitration to 9 mg on day 14) QD or investigator’s choice of chemo (docetaxel or vinflunine) Q3W until disease progression or intolerable toxicity. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Results: 266 pts were randomized: 136 pts assigned to erda, 130 to chemo. In all pts, median age was 67 y; 30% had 1 prior line of tx, 70% had 2 prior lines; 74% had visceral metastases; 90% were PD-L1 low (CPS <10). Median follow-up was 15.9 mo. The primary endpoint of the study was met, with erda significantly increasing OS and reducing the risk of death by 36%; median OS was 1 y (Table). These data met predefined stopping criteria for superiority. Erda also significantly improved median PFS (5.6 vs 2.7 mo) and ORR (46% vs 12%) vs chemo. No new safety signals were seen. Serious treatment-related adverse events (TRAEs) were observed in 13% and 24% of pts with erda and chemo, respectively, and grade (Gr) 3/4 TRAEs were observed in 46% and 46% of pts with erda and chemo, respectively. TRAEs leading to death were reported in 1 and 6 pts with erda and chemo, respectively. More TRAEs leading to dose reduction were observed with erda (66%) vs chemo (21%); 8% and 13% of pts had TRAEs leading to discontinuation of erda and chemo, respectively. Central serous retinopathy occurred in 23 pts (17%) with erda (Gr 1-2, 20 pts). Conclusions: In pts with FGFRalt advanced/mUC after prior treatment with PD-(L)1, erda significantly improved OS, PFS, and ORR vs investigator’s choice of chemo. Erda toxicity was consistent with the known safety profile. These results support the role of erda to treat pts with FGFRalt mUC after PD-(L)1 tx. Clinical trial information: NCT03390504 . [Table: see text]

Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results.

LBA3000 Background: T-DXd is an antibody drug conjugate targeting HER2 and is approved in HER2-expressing breast (BC) and gastric (GC) cancers. HER2 expression is prevalent in other solid tumors. The efficacy of current treatments (Tx) in these populations, including studies with HER2-directed Tx, is modest, revealing a significant unmet medical need. Clinically meaningful activity of T-DXd was seen in HER2-expressing tumors in a phase 1 study (NCT02564900). Methods: DP-02 (NCT04482309) is an open-label phase 2 study of T-DXd 5.4 mg/kg q3w in pts with HER2-expressing (immunohistochemistry [IHC] 3+ or IHC 2+ by local or central testing) locally advanced or metastatic disease that progressed after ≥1 systemic Tx or that has no Tx options. Cohorts with biliary tract (BTC), bladder (URO), cervical (CC), endometrial (EC), ovarian (OC), pancreatic (PC), or other tumors (excluding BC, GC, colorectal cancer, and non-small cell lung cancer) were enrolled. Efficacy and safety were analyzed in all pts who received ≥1 dose of T-DXd. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR), disease control rate, progression-free and overall survival, and safety. Results: At data cutoff (16 Nov 2022; median follow-up, 9.7 mo), 267 pts had been treated (median, 2 prior lines of Tx [range, 0-13]); 75 pts were IHC 3+ and 125 were IHC 2+ by central testing. In all 267 pts, the ORR was 37.1% and median DOR (mDOR) was 11.8 mo; in pts with IHC 3+ expression, the ORR was 61.3% and mDOR was 22.1 mo. ORR per cohort is shown in all pts and those with centrally confirmed HER2 IHC 3+ or IHC 2+ expression. Grade (G) ≥3 adverse events (AEs) occurred in 58.4% of pts; 11.6% discontinued Tx due to AEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 18 pts (6.7% [G1, n=6; G2, n=11; G5, n=1]). Conclusions: This is the first tumor-agnostic global study of T-DXd in a broad range of HER2-expressing solid tumors. T-DXd showed encouraging ORR, particularly in pts with IHC 3+ expression, durable clinical benefit, and a manageable safety profile in this heavily pretreated population. These interim results show T-DXd to be a potential new Tx option for pts with HER2-expressing solid tumors. Clinical trial information: NCT04482309 . [Table: see text]

Interim analyses (IA) of the giredestrant (G), G + abemaciclib (A), and G + ribociclib (R) arms in MORPHEUS Breast Cancer (BC): A phase I/II study of G treatment (tx) combinations in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced/metastatic BC (ER+, HER2– LA/mBC).

1061 Background: Limitations of current approved endocrine therapies (ETs), a mainstay tx for ER+ BC, include incomplete ER signaling inhibition. Novel ETs, such as selective estrogen receptor antagonists and degraders (SERDs), may help overcome this. G, a potent, nonsteroidal, oral (PO) SERD, is well tolerated and has shown robust ER occupancy and encouraging antitumor activity as monotherapy and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (P). MORPHEUS BC (NCT04802759) is evaluating the safety and efficacy of G tx combinations in ER+, HER2– LA/mBC. We present results from the 16-week IA of G and G + CDK4/6i (A or R). Methods: Eligible pts had disease progression on 1–2 lines of ET (including a CDK4/6i) for LA/mBC. Pts were randomized 1:6 (planned n = 15 per arm) to receive G (30 mg PO QD; control arm), G + A (150 mg PO BID), or sequentially, G + R (600 mg PO QD) until disease progression/unacceptable toxicity. The study was not designed to make explicit power and type I error considerations for a hypothesis test. Primary endpoints were safety and objective response rate; other endpoints included progression-free survival, overall survival, clinical benefit rate, disease control rate (DCR), duration of response, and pharmacokinetics. Genetic alterations were defined using baseline circulating tumor DNA. Results: As of Feb 4, 2022, 15 pts were enrolled in the G + A arm; 73% received one prior line of tx in the LA/mBC setting; 27% received prior fulvestrant; 73% had liver metastases at baseline (BL). As of Sept 22, 2022, 11 and 16 (of whom 14 were evaluable) pts were enrolled in the G and G + R arms, respectively; 64%/86% received one prior line of tx in the LA/mBC setting; 73%/36% received prior fulvestrant; 73%/57% had liver metastases at BL. Three pts had a partial response (PR; G + A, n = 1; G + R, n = 2); 19 had stable disease (G, n = 5; G + A, n = 7; G + R, n = 7). DCRs were 36% (G), 40% (G + A), and 50% (G + R). Safety is shown. Conclusions: G combined with a CDK4/6i (A or R) was well tolerated, with no unexpected safety signals. Three PRs were seen in this heavily pretreated population of pts with disease progression post-CDK4/6i tx. This study provides the first data supporting the combinability of G with the CDK4/6is A and R, in addition to P as seen in prior studies. G can therefore be combined with all three approved CDK4/6is. Clinical trial information: NCT04802759 . [Table: see text]

First-in-human dose-escalation trial of BI 764532, a delta-like ligand 3 (DLL3)/CD3 IgG-like T-cell engager in patients (pts) with DLL3-positive (DLL3+) small-cell lung cancer (SCLC) and neuroendocrine carcinoma (NEC).

8502 Background: The inhibitory Notch ligand, DLL3, is highly expressed on the cell surface of SCLC and NEC tumors and is a promising drug target. BI 764532 is a DLL3/CD3 T cell engaging bispecific antibody that has shown potent preclinical anti-tumor activity in DLL3+ cells and xenograft models. NCT04429087 is an ongoing phase I first-in-human, open-label, dose-escalation trial of BI 764532 in adults with locally advanced/metastatic DLL3+ (confirmed centrally) SCLC, NEC or small cell carcinoma of any other origin (grouped as NEC), or large cell NEC (LCNEC). Methods: BI 764532 was administered intravenously using three different regimens: Regimen (R) A (fixed iv dose q3w); RB1 (fixed iv dose qw); RB2 (step-in doses followed by a fixed dose). Treatment (Tx) continued until progressive disease (PD), unacceptable toxicity, other withdrawal criteria, or maximum Tx duration (36 mos). The main objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion of BI 764532, based on dose-limiting toxicities (DLTs) during the MTD evaluation period. Further objectives were safety, tolerability, PK/PD and preliminary efficacy based on investigator review (RECIST v1.1). Results: As of 28th Dec 2022, 90 pts received ≥1 dose of BI 764532 (RA: n = 24, 8 dose levels; RB1: n = 10, 3 dose levels; RB2: n = 56, 6 dose levels; starting dose: 0.03 µg/kg). Median age: 60 years (32–78); ECOG PS 0/1: 24/74%; prior PD1/PD-L1 Tx: 40%; ≥2 prior lines of Tx: 69%. SCLC/NEC/LCNEC: 52/41/4%. Median Tx duration: 43 days (range 1–443); 25 pts are ongoing. DLTs were seen in 1 pt on RA (Grade 3 confusion) and 4 pts on RB2 (Grade 4 cytokine release syndrome [CRS]; Grade 3 CRS, Grade 3 nervous system disorder, Grade 2 infusion-related reaction). MTD has not been reached and dose escalation is ongoing. Overall, the most common treatment-related AEs were (any/Grade 3+): CRS (58/2%); pyrexia (19/0%); decreased lymphocytes (18/14%); asthenia (17/1%); dysgeusia (14/0%). CRS was managed with supportive care, corticosteroids, and/or anti-IL-6R antibodies. With RB2, most CRS and neurological events occurred early, and were reversable. Tumor response data were available for 70 pts (RA/RB1/RB2: n = 19/8/43). In pts with SCLC (n = 24) or NEC (n = 23) who received ≥ target dose of BI 764532, ORR was 33% and 22% across all regimens, respectively. One pt with LCNEC was also evaluable for response and achieved PR. Conclusions: BI 764532 showed clinically manageable tolerability and MTD has not been reached at the doses administered to date. Promising efficacy has been observed, not only in SCLC but also in difficult to treat entities such as NEC and LCNEC. The study is ongoing; updated data will be presented. Clinical trial information: NCT04429087 .

Phase 1b OMNIVERSE trial: Safety and tolerability of oral azacitidine (Oral-AZA) in combination with venetoclax (VEN) for treatment of acute myeloid leukemia.

e19011 Background: Safer and more effective lower-intensity treatment (Tx) options are needed for patients (pts) with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC). The combination of VEN, an oral BCL-2 inhibitor, and injectable AZA (Inj AZA), a hypomethylating agent, is indicated in IC-ineligible pts with newly diagnosed (ND) AML and has shown significantly improved response and survival rates vs. Inj AZA alone (DiNardo et al., N Engl J Med 2020). Oral-AZA allows for extended dosing schedules vs. Inj AZA. Methods: OMNIVERSE (NCT04887857) is an ongoing, phase 1b, multicenter, open-label, dose-determination study evaluating Oral-AZA + VEN in pts with relapsed/refractory (R/R; part 1) and ND AML (part 2). This abstract presents data from part 1. Eligible pts are adults with R/R AML (WHO 2016 criteria) not eligible for further IC, with an ECOG performance status of ≤ 2. The Oral-AZA starting dose is 300 mg QD × 14 days (d) per 28d cycle (dose level [DL] −1), which can be de-escalated to 200 mg QD × 14d depending on dose-limiting toxicities (DLTs); VEN 400 mg QD is taken continuously (or 21d per cycle; DL −2). Dosing decisions are guided by a modified toxicity probability interval 2 (mTPI-2) design. The primary endpoint is to evaluate safety/tolerability and establish the maximum tolerated dose (MTD) of Oral-AZA + VEN in R/R AML (starting dose for part 2). Secondary endpoints are to assess preliminary investigator-determined response rates per ELN 2017 AML response criteria (Döhner et al., Blood 2017) for complete remission (CR), CR with partial hematologic recovery, CR with incomplete blood count recovery (CRi), morphologic leukemia-free state, overall response, and measurable residual disease (plus conversion rate). Results: Pt enrollment began in December 2021 and is ongoing; data from part 1 are available for 5 pts (3 female; aged 51–80 years). 3 pts had 1 prior line of Tx and 2 pts had 2. Oral-AZA + VEN was given for 1–12 cycles. Of the 5 pts, 3 reported ≥ 1 any grade (Gr) drug-related adverse event, the most common of which were Gr 1–3 diarrhea (2 pts) and Gr 1–2 nausea (2 pts). Gr 3 febrile neutropenia, which was not deemed drug related, was reported in 4 pts (6 episodes total). In 1 pt, Oral-AZA was reduced to 200 mg QD x 14d from cycle 4 due to Gr 1 diarrhea and VEN to 70 mg QD x 28d from cycle 3 due to co-Tx with a strong CYP3A inhibitor (per protocol). 3 pts died after Tx discontinuation. No DLTs were observed and MTD of Oral-AZA + VEN was determined to be Oral-AZA 300 mg QD x 14d + VEN 400 mg QD x 28d. As of January 2023, 2 pts remained on Tx and best response achieved was CRi in 2 pts and stable disease in 3 pts. Conclusions: These results indicate that a MTD of Oral-AZA 300 mg QD x 14d + VEN 400 mg QD x 28d has a manageable safety profile consistent with known profiles of the 2 agents. Further evaluation in AML is warranted. Clinical trial information: NCT04887857 .

Phase II study of pembrolizumab plus mifepristone in patients with advanced HER2-negative breast cancer.

1095 Background: Metastatic breast cancer is incurable, and novel treatment (tx) strategies are needed. Single agent immune checkpoint inhibitor (ICI) tx has limited efficacy; combination approaches may yield better results. Multiple mechanisms of glucocorticoid-induced immunosuppression have been proposed, including the suppression of the cytotoxic Th1 cytokine response via glucocorticoid receptor (GR) activation. We hypothesize that pretreatment with a GR antagonist shifts the cytotoxic immune response toward Th1, thus enhancing response to ICIs. We present the safety and efficacy of the combination of pembrolizumab and mifepristone in advanced HER2-negative breast cancer. Methods: This (NCT03225547) was a phase II non-randomized study of pembrolizumab and mifepristone in patients (pts) with advanced HER2-negative breast cancer. Pts with prior ICI tx were excluded. Pts received mifepristone 300mg daily and pembrolizumab 200mg every 3 weeks; mifepristone was started 7 days prior to pembrolizumab. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety and tolerability. Results: 18 patients were enrolled from March 2018 – November 2020; 10 patients with TNBC (cohort 1) and 8 patients with HR+ BC (cohort 2). Mean age was 53 yrs (range 33-74) and 33% of patients were self-reported Black. In cohort 1, 50% of patients were tx naive in this advanced setting, and 90% of patients had < 2 prior lines of tx. In cohort 2, 25% of patients had not received prior chemo in the metastatic setting. The overall ORR was 6%. One pt with TNBC had a complete response (CR). She received 36 cycles of tx; tx was discontinued due to mucositis and rash, and she remains in CR at >48 mos from start of tx. No patients in cohort 2 had a partial or complete response. The most common treatment-related adverse events were rash (61%), thyroid abnormality (17%), and pruritis (17%). 45% of patients experienced a grade 3 or 4 adverse event; all except one (hypokalemia) were due to rash. Rash was described as maculopapular dermatitis. The DCR at 18 weeks was 33.3% in the overall population; it was 44.4% in cohort 1 and 16.7% in cohort 2. Overall median PFS was 1.9 months [95% CI 1.8 – 3.6]. Overall median OS was 12.9 months [95% CI 5.8 – 23.0]. Conclusions: While this regimen demonstrated efficacy in a small subset of patients, including one pt with long-term CR, given the non-randomized design, we cannot determine if mifepristone enhanced the efficacy of ICI. In addition, a higher than anticipated rate of skin toxicity, possibly related to mifepristone enhancing the activity of ICI, was observed in the study, leading to early closure. While the benefit/risk analysis of this combination does not support further evaluation, additional investigation of alternative chemotherapy-free, immunomodulatory strategies is warranted. Clinical trial information: NCT03225547 .

Subgroup analyses of safety and efficacy by number and types of prior lines of treatment in FRESCO-2, a global phase III study of fruquintinib in patients with refractory metastatic colorectal cancer.

3604 Background: Effective treatment options are limited for patients (pts) with refractory metastatic colorectal cancer (mCRC). Fruquintinib (F), a highly selective, potent, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3, was evaluated in the global phase III FRESCO-2 study (NCT04322539) and demonstrated a clinically meaningful and statistically significant improvement in OS and PFS with a favorable safety profile. Here we report subgroup analyses of efficacy and safety by prior lines (PL) and types of anti-cancer treatment (Tx) for metastatic disease (MD). Methods: FRESCO-2 was conducted in the US, Europe, Japan & Australia, comparing F + best supportive care (BSC) with Placebo (P) + BSC. Pts were given 5 mg PO, QD, 3 wks on, 1 wk off, in a 28-day cycle. Eligible pts received prior chemotherapy, anti-VEGF, and if RAS wild type, anti-EGFR therapies; if BRAFV600E mutant or MSI-H, and appropriate targeted regimen; and had progressed on, or were intolerant to, trifluridine/tipiracil (TAS-102) and/or regorafenib (R). Subgroup (sbgrps) analyses for efficacy and safety were performed according to number of prior lines of tx (LOT) and by types of therapy. Results: A total of 691 pts were randomized; F:461 vs P:230. The median number of prior lines of anti-cancer tx for metastatic disease F vs P was 4 (2, 16) vs 4 (2, 12). F improved OS and PFS compared to P for all sbgrps and prior tx for MD, consistent with those of the ITT population (pop). (Table: OS reported by sbgrps and prior tx for MD). Occurrence of adverse events (AEs) and serious adverse events were generally balanced between F vs P and consistent across all subgroups. The most common ≥ G3 AEs in ≥5% of pts on F within majority of sbgrps were hypertension, asthenia and palmar plantar erythrodysesthesia and were consistent with the overall safety population. Additional analyses based on duration of prior anti-VEGF and last therapy prior to F will be presented at the conference. Conclusions: F demonstrated clinically meaningful improvement in OS, PFS with an acceptable safety profile across all sbgrps. These results were consistent with the effect observed in the overall population; irrespective of previous tx with anti-VEGF, anti-EGFR, TAS-102 and R further supporting F as a potential new tx option for pts with refractory mCRC. Clinical trial information: NCT04322539 . [Table: see text]

Effect of follow-up time on the ability of subcutaneous epcoritamab to induce deep and durable complete remissions in patients with relapsed/refractory large B-cell lymphoma: Updated results from the pivotal EPCORE NHL-1 trial.

7525 Background: Outcomes are poor for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Effective treatments (tx) that drive deep, durable responses and long-term benefit are needed. In the pivotal EPCORE NHL-1 trial (NCT03625037), single-agent epcoritamab (epcor) showed high complete response (CR) and MRD-negativity rates, a median duration of response (mDoR) not reached (NR) in pts who achieved CR, and a manageable safety profile as an off-the-shelf, subcutaneous (SC), CD3xCD20 T-cell–engaging bispecific antibody (Thieblemont et al, JCO 2022). We present updated results with longer follow-up in a challenging-to-treat population. Methods: Pts with R/R CD20+ LBCL received SC epcor (step-up priming and intermediate doses followed by 48-mg full doses) in 28-d cycles (Cs): QW, C1–3; Q2W, C4–9; Q4W, C≥10 until PD or unacceptable toxicity. Results: As of Nov 18, 2022, of 157 pts (median age, 64 y) with LBCL (including DLBCL [n=139], HGBCL [n=9], PMBCL [n=4], and FL grade 3B [n=5]; 13/99 double/triple-hit by FISH), 36 remain on tx. Pts had a median of 1.6 y from initial diagnosis to first dose and a median of 3 (range, 2–11) prior tx lines; 61% of pts had primary refractory disease, and 39% had prior CAR T, of whom 75% progressed ≤6 mo of tx. Median follow-up was 20 mo (range, 0.3+ to 28.2). Pts received a mean of 9.1 cycles. LBCL overall response and CR rates were 63.1% and 39.5%, respectively, and were consistent for DLBCL (61.9% and 39.6%). The mDoCR was 20.8 mo. Median time to CR was 2.7 mo; 8 pts converted from partial response to CR at ≥36 wk. Median overall survival (mOS) was 18.5 mo (95% CI, 11.7–NR), with an estimated 58% of pts alive at 12 mo. mOS was NR in pts who achieved CR. Additional outcomes for pts with CR are shown in Table. The most common TEAEs of any grade (G) were: CRS 51%, neutropenia 24%, pyrexia 24%, fatigue 23%, nausea 22%, and diarrhea 21%. Nine pts (6%) had G1–2 ICANS, and 1 pt had a G5 event with confounding factors. Fatal TEAEs occurred in 15 pts; 2 were considered related (COVID-19, ICANS). CRS was predominantly low grade (48% G1–2; 3% G3) and occurred following the first full dose (C1D15). One pt discontinued tx due to G1 CRS. Total metabolic tumor volume (TMTV) data will be presented. Conclusions: These data with longer follow-up reaffirm single-agent SC epcor induces durable CRs with improved outcomes and a manageable safety profile. No new safety signals were observed in these hard-to-treat pts. These impressive data support the ongoing phase 3 studies evaluating epcor across different lines of tx and in various combinations. Clinical trial information: NCT03625037 . [Table: see text]

Updated phase I study results of PHE885, a T-Charge manufactured BCMA-directed CAR-T cell therapy, for patients (pts) with r/r multiple myeloma (RRMM).

8004 Background: B cell maturation antigen (BCMA) targeted CAR-T cells are approved for RRMM. Long manufacturing time and high clinical demand limit access. T-Charge, an innovative platform that reduces manufacturing time to <2 days and preserves T cell stemness, results in robust expansion and prolonged CAR T cell persistence. Here we report updated results from the Phase I trial of T-Charge manufactured, fully human, BCMA CAR-T PHE885 (NCT04318327). Methods: Eligible pts had RRMM after ≥2 prior lines of therapy (tx). Pts received fludarabine and cyclophosphamide (or bendamustine) for lymphodepletion (LD) prior to PHE885 infusion. Primary objective was safety. Secondary objectives were clinical response and cellular kinetics. Results: As of December 22, 2022, 46 pts received PHE885 at the following doses: 2.5e6 (n=4), 5e6 (n=13), 10e6 (n=20), 14.3e6 (n=1), and 20e6 (n=8) CAR T cells. PHE885 was manufactured for 61% of pts at a single academic institution; these pts proceeded from apheresis to LD in a median of 16 days. Median age at enrollment was 65 y (range [R] 45-81), median prior lines of tx was 4 (R 2-10). 37% of pts had extramedullary disease; 96% were triple refractory. Despite aggressive disease, only 28% of pts required bridging chemotherapy, predominantly influenced by quick production time. 96% of pts experienced any gr cytokine release syndrome (CRS); 11% had gr 3 CRS. Median time to CRS onset was 8 (R 2-16) days and median duration was 4 (R 1-19) days. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 22% of pts; 7% had gr 3 ICANS. Dose limiting toxicities were experienced by 13% of pts and included gr 4 neutropenia, gr 4 lipase increase, gr 3 serum amylase increase, gr 3 neurotoxicity, gr 3 transaminitis, and gr 3 ejection fraction reduction. The most common tx-related gr ≥3 AEs included anemia (54%), neutropenia (50%), and thrombocytopenia (37%). Geo-mean peak PHE885 expansion (Cmax) was 276,000 copies/µg by qPCR and 70.6% of CD3+ T cells by flow cytometry (n=41). The PHE885 transgene was detected in 13/14 (93%) pts at 6 mo and 5/7 (71%) at 12 mo post infusion. T cells with early memory phenotype were preserved in the final product and persisted in pts post infusion. In 43 efficacy-evaluable pts, the ORR was 98%. At 10e6 dose (n=19), ORR was 100% and CRR was 42% (median follow-up of 4.9 mo [R 1.4-11.8]); 60% of 10 evaluable pts were MRD negative at 10-5 by NGS. Initial efficacy data at 20e6 and longer follow-up at active doses will also be presented. Conclusions: T-Charge manufactured PHE885 produced high response rates with no unexpected safety findings in heavily pretreated RRMM pts with aggressive disease. PHE885 expanded rapidly and showed durable persistence in vivo. Since conversion to CR/sCR has occurred as late as 18 months after infusion in this study, longer follow-up is ongoing to identify a recommended dose for future development. Clinical trial information: NCT04318327 .

EXCALIBER-RRMM: A phase 3, two-stage study of iberdomide, daratumumab, and dexamethasone (IberDd) versus daratumumab, bortezomib, and dexamethasone (DVd) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).

TPS8069 Background: New treatments (Txs) are needed to achieve deep and durable responses in RRMM. Iberdomide (IBER) is a novel, potent oral cereblon E3 ligase modulator (CELMoD) with enhanced tumoricidal and immune-stimulatory effects compared with immunomodulatory drugs (IMiDs). IBER has synergy with dexamethasone (DEX), daratumumab (DARA), and bortezomib (BORT) in vitro. In a phase 1/2 trial, IberDd demonstrated efficacy with a manageable safety profile in pts with RRMM (Lonial S, et al. HemaSphere 2021;5(S2):S187). The EXCALIBER-RRMM phase 3 trial (NCT04975997) will compare the efficacy and safety of IberDd with that of DVd in pts with early RRMM. Methods: This multicenter, open-label study will be conducted in 2 stages: in Stage 1, ≥ 200 pts will be randomized 1:1:1:1 to 1 of 3 IBER doses (1.0, 1.3, or 1.6 mg) + DARA and DEX or to the DVd arm to identify optimal IBER dose when combined with DARA + DEX; in Stage 2, ≈ 664 additional pts will be randomized 1:1 to IberDd at the selected IBER dose or to DVd, for efficacy and safety analyses (Stage 1 pts in IBER selected dose cohort and DVd arm to be also included). Pts will be stratified by number of prior Tx lines (1 vs 2), age (≤ 70 vs > 70 y), and ISS stage at study entry (I–II vs III). Primary efficacy endpoint is progression-free survival (PFS), which is defined as the time from randomization to progressive disease (PD) or death. Assuming a decrease in PFS risk by 25% (HR = 0.75) with IberDd, under exponential distribution assumption of PFS (1-sided α = 0.025) and adjusted for 3 interim analyses, 458 PFS events will have ≈ 84% power to detect an improvement in Tx effect. The 3 planned interim analyses are: for IBER dose selection at end of Stage 1; and to examine PFS futility and superiority when ≈ 138 (30%) and ≈ 344 (75%) events, respectively, have been accumulated. Secondary endpoints include overall survival, duration of response, time to progression, overall response rate, measurable residual disease negativity rate, safety, and quality of life. Tx in the IberDd arm will consist of 28-day (D) cycles (C) with IBER on D1–21; 1800 mg subcutaneous (SC) DARA on D1, 8, 15, and 22 of C1–2, D1 and 15 of C3–6, and D1 of ≥ C7; and 40 mg oral DEX (20 mg in pts > 75 y of age) on D1, 8, 15, and 22. Tx in the DVd arm will consist of 21-D cycles for C1–8 and 28-D cycles for ≥ C9; 1800 mg SC DARA on D1, 8, and 15 for C1–3, D1 for ≥ C4; 1.3 mg/m² SC BORT on D1, 4, 8, and 11 for C1–8; and 20 mg oral DEX (10 mg in pts > 75 y of age) on D1, 2, 4, 5, 8, 9, 11, and 12 for C1–8. Tx will continue until confirmed PD, unacceptable toxicity, or consent withdrawal. Key eligibility criteria include age ≥ 18 y, 1–2 prior lines of antimyeloma Tx, partial response or better to ≥ 1 prior Tx, and documented PD during or after the last regimen. Prior anti-CD38 Tx is allowed only in Stage 2 (≤ 10% of pts). Enrollment began in June 2022 and is currently ongoing. Clinical trial information: NCT04975997 .

Abstract CT013: Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMA×CD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma

Abstract Background: MM remains incurable and new tx options are needed, especially in heavily pre-treated R/R pts. REGN5459, a BCMAxCD3 bispecific Ab, binds to BCMA on MM cells and with low affinity to CD3 on T cells, triggering T-cell activation and plasma cell depletion with low cytokine release preclinically. This first-in-human study aimed to assess the safety, tolerability, and preliminary anti-tumor activity of REGN5459 monotherapy in pts with R/R MM. Methods: Eligible pts had received ≥3 prior lines of tx including an anti-CD38 Ab, proteasome inhibitor, and immunomodulatory drug, and had exhausted all available tx options. Pts could receive REGN5459 until progression/intolerable toxicity. Primary objectives were to assess safety, tolerability, dose limiting toxicities (DLTs), and determine the recommended Ph 2 dose (RP2D) of REGN5459 (Ph 1) and assess efficacy of REGN5459 (Ph 2) per ORR. Results: As of June 9, 2022, 43 pts were enrolled (Ph 1, 33; Ph 2, 10): median age 67 yrs (range, 26-85), 51% female, 16% high cytogenetic risk, 14% extramedullary plasmacytoma, 37% R-ISS Stage III disease, 61% triple-class refractory, and median of 5 (range, 2-9) prior lines of tx. In Ph 1, one DLT was reported in a pt receiving the highest dose (900 mg; Gr 3 hypoxia, pt later found to have primary lung cancer). RP2D was identified as 480 mg. All pts enrolled had ≥1 TEAE, 74% had Gr ≥3 TEAEs. TEAEs all-Gr in ≥30% of pts were CRS (54%), fatigue (44%), neutropenia (37%), anemia (35%), cough (30%), and diarrhea (30%). Gr ≥3 TEAEs in ≥15% of pts were neutropenia (37%), anemia (26%), lymphopenia (23%), thrombocytopenia (19%), and hypertension (16%). CRS Gr 1, 2, and 3 were reported in 47%, 2%, and 5%, respectively; there was no Gr 4 or 5 CRS. No Gr 3 CRS with RP2D. Tocilizumab was used in 19% and steroids in 9% of pts. One pt developed ICANS (2%, Gr 2). Incidence of serious TEAEs and TEAEs leading to tx discontinuation was 63% and 16%. Infections occurred in 61% (37% Gr ≥3). After data-cutoff, two deaths due to COVID pneumonia and COVID infection have been reported. ORR was 67% (58% ≥VGPR) for the entire cohort and 100% (85% ≥VGPR; 15% sCR; 39% CR) among pts receiving the RP2D (n=13). Median follow-up was 7 mos (range, 1-26) with longest response ongoing for 22+ mos. Median time to response was 0.8 mos. Median DOR was NR (95% CI, 12-NE); 12-mo DOR for RP2D was 66.7% (95% CI, 5.4-94.5). Of pts in ≥CR with available MRD results (n=8), 50% were MRD negative at the 10−5 threshold. Conclusion: These initial data show that REGN5459 has acceptable safety/tolerability in R/R MM with most CRS of low grade and low incidence of ICANS. Modulation of CD3 affinity on bispecific Abs to maximize tumor killing, and mitigate CRS and T-cell exhaustion, warrants further research. Efficacy in this heavily pre-treated cohort was encouraging, with 100% ORR with the RP2D. Updated data will be presented at the meeting. Citation Format: Attaya Suvannasankha, Prashant Kapoor, Matthew J. Pianko, Joshua Richter, Anita D'Souza, Larry D. Anderson, Andrew Magyar, Oluwaseun Aina, Anita Boyapati, Damien Cronier, Nikhil Singh, Karen Rodriguez-Lorenc, Glenn S. Kroog, Hans C. Lee. Safety and efficacy from the phase 1/2 first-in-human study of REGN5459, a BCMA×CD3 bispecific antibody with low CD3 affinity, in patients with relapsed/refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT013.

Preliminary Dose-Escalation Results from a Phase 1/2 Study of GEN3014 (HexaBody®-CD38) in Patients (pts) with Relapsed or Refractory Multiple Myeloma (RRMM)

Background: CD38-targeted antibodies (Abs) are foundational treatments (Tx) for pts with newly diagnosed or RRMM. GEN3014 (HexaBody®-CD38) is a novel human IgG1 anti-CD38 monoclonal Ab (mAb) with an E430G hexamerization-enhancing mutation that facilitates highly efficient complement-dependent cytotoxicity (CDC). GEN3014 showed preclinical tumor cell killing through highly potent CDC (more efficient than daratumumab) and Ab-dependent cellular cytotoxicity and phagocytosis. We present preliminary data from dose escalation in the first-in-human, phase 1/2 trial of GEN3014 in pts with RRMM (NCT04824794). Methods: Adults with RRMM were enrolled if they had ≥3 prior lines of Tx including a proteasome inhibitor (PI) and an immunomodulatory imide drug (IMiD), were double refractory to a PI and IMiD, or had ≥2 prior lines of Tx if 1 combined a PI and IMiD. GEN3014 was tested at 6 dose levels ranging from 0.2 to 24 mg/kg and administered intravenously in 28-d cycles (first dose split equally between D1 and D2 of cycle 1, then full doses QW through cycle 2; Q2W, cycles 3-6; Q4W, cycles ≥7). Primary objectives were to determine the recommended phase 2 dose (RP2D) and maximum tolerated dose. Other endpoints included pharmacokinetic (PK) and pharmacodynamic (PD) characterization. PD biomarker analysis included immunophenotyping and quantification of complement factors and cytokines in peripheral blood. Results: As of July 10, 2022, 24 pts with RRMM were treated (median age, 65 y; range, 45-84). Pts were heavily pretreated with a median of 7 prior lines of Tx (range, 3-13). Most pts (67%) had prior exposure to a daratumumab- or isatuximab-containing regimen, with 8 pts naive to anti-CD38 mAb. GEN3014 was well tolerated; the most common Tx-emergent AEs were infusion-related reactions (IRRs; 75.0%), neutropenia (62.5%), anemia (33.3%), diarrhea (33.3%), pyrexia (25.0%), and thrombocytopenia (25.0%). IRRs were mostly low grade (G; 62.5% G1-2, 12.5% G3, no G4), occurred mainly during the first infusion, and were manageable. There were no Tx-related deaths or dose-limiting toxicities observed at doses up to 16 mg/kg, the RP2D. Disease progression led to discontinuation in 80% of pts. Among 19 response-evaluable pts (5 naive to anti-CD38 mAb, 14 refractory to anti-CD38 mAb), preliminary antitumor activity was seen. In pts naive to anti-CD38 mAb, 2 pts achieved very good partial response (1 each at 4 and 24 mg/kg); 1 achieved minimal response (MR; 16 mg/kg). In pts refractory to anti-CD38 mAb, 2 pts achieved MR (1 each at 8 and 16 mg/kg). Five pts remained on Tx (4 naive and 1 refractory to anti-CD38 mAb). Updated data will be presented. Peak GEN3014 concentrations at the end of infusion increased roughly proportionally with dose. The interval area under the concentration-time curve showed a more than proportional increase with doses ≤8 mg/kg but a proportional or less than proportional increase at doses >8 mg/kg. These results suggest target-mediated drug disposition at lower doses and a high degree of target saturation at >8 mg/kg. Trough concentrations increased with weekly administration, most notably in pts responding to Tx, indicating target cell depletion over time. GEN3014 Tx was associated with a rapid, sustained decrease in peripheral blood natural killer cells at all doses in all pts (mean 92.4% ± 9.2% peak reduction from baseline [BL], n=21). T cells transiently decreased after administration of first doses ≥4 mg/kg, followed by expansion (≥100% increase from BL), particularly in pts naive to anti-CD38 mAb. GEN3014 induced transient reduction in complement component C2 (mean 58% ± 18% peak reduction from BL, n=18) and total complement lytic activity (CH50; mean 48% ± 24% peak reduction from BL for ≥8 mg/kg, n=11) at all evaluable doses, suggesting CDC. Complement parameters rapidly returned to BL, indicating that Tx does not exhaust complement. Plasma cytokine (IL-2, IL-6, IL-8, IL-10, IFNγ, and TNFα) levels generally remained low after Tx. Conclusions: Dose-escalation results show GEN3014 had a tolerable safety profile and clinical activity in pts with RRMM, including pts with prior anti-CD38 mAb. The PK profile is characterized by target-mediated drug disposition at lower doses and signs of saturation at doses >8 mg/kg. Biomarker analyses confirm biological activity in pts with RRMM at all evaluated doses. The expansion part of the trial evaluating the 16 mg/kg RP2D is ongoing.