Prior Lines Of Therapy Research Articles

Real-World Treatment Patterns, Survival, and Economic Burden Among Elderly MCL Patients Previously Treated With cBTKis

BackgroundWhile covalent Bruton's tyrosine kinase inhibitors (cBTKis) have become a standard of care treatment for relapsed/refractory mantle cell lymphoma (R/R MCL), response duration is limited and resistance to BTKi and/or adverse events develop in a subset of patients. However, little real-world evidence on post-cBTKi clinical and economic outcomes exists for these patients. Patients and MethodsThis retrospective study used 2010 to 2019 U.S. Medicare claims, to identify elderly (≥ 66 years) patients with newly-diagnosed MCL who received third-line (3L) treatment and had evidence of cBTKi use in a prior line of therapy. Outcomes were assessed ≥ 12-months post 3L-treatment initiation and included treatment patterns, all-cause and MCL-related HRU and costs, and overall survival. ResultsThe final sample contained 230 elderly patients with R/R MCL receiving 3L treatment who had cBTKi use in a prior line of therapy (mean age 75.0, 21.7% age > 80 years; 67.4% male; 93.9% White). Common 3L treatments included chemotherapy (26.1%), lenalidomide (18.7%), and bortezomib (18.3%); 1-quarter (25.7%) of patients received a cBTKi (17.8% ibrutinib; 7.8% acalabrutinib). Overall survival was poor from 3L treatment initiation (median OS = 9.4 months; 1-years survival rate = 43.7%). Patients exhibited high rates of HRU (73.6% experienced hospitalization) and substantial costs ($145,726) in the 12-months after 3L initiation. ConclusionA large unmet need exists in this patient subpopulation, highlighting the importance of ongoing development of novel therapeutics.

Factors associated with response to talimogene laherparepvec in the treatment of advanced melanoma

Talimogene laherparepvec (T-VEC) is currently the only United States Food and Drug Administration-approved intralesional therapy for advanced melanoma. Recent studies have assessed the integration of T-VEC with systemic immunotherapy, though the response remains variable. Therefore, we sought to identify factors associated with the response to T-VEC by conducting a retrospective, single-center analysis involving melanoma patients treated with T-VEC. In the present study, we recorded demographic and clinicopathological data, details of T-VEC treatments, prior and concurrent treatments, and clinical outcomes. The primary endpoint was the in-field overall response rate (ORR: complete + partial). Secondary endpoints included complete in-field response, defined as complete resolution of disease or a negative biopsy; disease failure-free survival (DFFS), defined from the initiation of treatment as the time to progression in patients who did not experience a disease-free interval and time to recurrence in those who did; and overall survival (OS). We used two-sample t-tests for continuous variables and Fisher’s exact test for categorical variables. DFFS and OS were further analyzed using the Kaplan–Meier method and log-rank tests for selected variables. Among the 18 patients who met the inclusion criteria, an in-field response was observed in 14 (78%) patients. Low disease burden (<5 lesions or a total diameter <5 cm) was associated with a higher in-field ORR compared to high-burden disease (100% vs. 43%, P = 0.01). There was a trend toward decreased in-field ORR for patients with >2 prior lines of systemic therapy (P = 0.18). With a median follow-up of 386 days, DFFS was associated with BRAF wild-type melanoma (P = 0.04), an in-field ORR (P = 0.007), and a measurable bystander response (P = 0.01). Two or more prior lines of immunotherapy were associated with poorer survival (P = 0.006) and worse DFFS (P = 0.02). In conclusion, despite a low sample size, we identified covariates associated with in-field ORR, DFFS, and OS, warranting further study.

Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study

An unmet need exists for patients with relapsed/refractory (R/R) follicular lymphoma (FL) and high-risk disease features, such as progression of disease within 24 months (POD24) from first-line immunochemotherapy or disease refractory to both CD20-targeting agent and alkylator (double refractory), due to no established standard of care and poor outcomes. Chimeric antigen receptor (CAR) T cell therapy is an option in R/R FL after two or more lines of prior systemic therapy, but there is no consensus on its optimal timing in the disease course of FL, and there are no data in second-line (2L) treatment of patients with high-risk features. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product. The phase 2 TRANSCEND FL study evaluated liso-cel in patients with R/R FL, including 2L patients who all had POD24 from diagnosis after treatment with anti-CD20 antibody and alkylator ≤6 months of FL diagnosis and/or met modified Groupe d’Etude des Lymphomes Folliculaires criteria. Primary/key secondary endpoints were independent review committee–assessed overall response rate (ORR)/complete response (CR) rate. At data cutoff, 130 patients had received liso-cel (median follow-up, 18.9 months). Primary/key secondary endpoints were met. In third-line or later FL (n = 101), ORR was 97% (95% confidence interval (CI): 91.6‒99.4), and CR rate was 94% (95% CI: 87.5‒97.8). In 2L FL (n = 23), ORR was 96% (95% CI: 78.1‒99.9); all responders achieved CR. Cytokine release syndrome occurred in 58% of patients (grade ≥3, 1%); neurological events occurred in 15% of patients (grade ≥3, 2%). Liso-cel demonstrated efficacy and safety in patients with R/R FL, including high-risk 2L FL. ClinicalTrials.gov identifier: NCT04245839.

IDeate-Lung02: A phase 3, randomized, open-label study of ifinatamab deruxtecan (I-DXd) vs treatment of physician’s choice (TPC) in relapsed small cell lung cancer (SCLC).

TPS8126 Background: SCLC is an aggressive malignancy, and patients (pts) with extensive stage (ES)-SCLC have a relatively short median overall survival (OS), with limited treatment options beyond first-line (1L) therapy. B7 homolog 3 (B7-H3 [CD276]) is a transmembrane protein expressed in many solid tumors but with low/no expression in normal tissue. In SCLC, B7-H3 is highly expressed and associated with poor prognosis and lack of response to standard therapy. I-DXd is a B7-H3-directed antibody–drug conjugate comprising an anti-B7-H3 mAb linked to a topoisomerase I inhibitor payload (DXd) via a stable cleavable linker, designed to enhance selective tumor cell death and reduce systemic exposure. I-DXd demonstrated durable efficacy (objective response rate [ORR] 52.4%; median duration of response [DoR] 5.9 mo; median OS 12.2 mo) irrespective of B7-H3 status, with a manageable safety profile in 21 ES-SCLC pts with a median of 2 prior lines of therapy in a Phase 1/2 trial (NCT04145622). I-DXd is being investigated in an ongoing Phase 2 trial in pretreated ES-SCLC, IDeate-Lung01 (NCT05280470). We describe a Phase 3 trial comparing the efficacy and safety of I-DXd vs TPC in relapsed SCLC. Methods: IDeate-Lung02 (NCT06203210) is a global, multicenter, randomized, open-label, Phase 3 trial in adult pts with relapsed SCLC who have received 1 prior line of platinum-based therapy and have an ECOG PS of ≤1; pts with asymptomatic brain metastases are eligible. Pts are randomized 1:1 to receive I-DXd 12 mg/kg iv every 3 wks (n = 234) or TPC (n = 234; topotecan, amrubicin, or lurbinectedin). Randomization is stratified by chemotherapy-free interval after 1L therapy (< 90 vs ≥90 days); TPC (topotecan vs amrubicin vs lurbinectedin); prior treatment with PD-(L)1 (yes vs no); and presence/history of asymptomatic brain metastases (yes vs no). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 wks for 48 wks, then every 12 wks. Dual primary efficacy endpoints are ORR per RECIST v1.1 by blinded independent central review (BICR) and OS. Secondary efficacy endpoints are ORR per investigator; progression-free survival, DoR, disease control rate and time to response by BICR and investigator; and patient-reported outcomes. Safety endpoints include incidence of treatment-emergent adverse events (TEAEs), deaths, serious TEAEs, and TEAEs leading to dose modification or discontinuation. Immunogenicity of I-DXd and relationship between B7-H3 expression and clinical outcome are also secondary objectives. ORR will be analyzed using a Cochran-Mantel-Haenszel test at a 2-sided 1% alpha level, and OS will be analyzed using a log-rank test at a 2-sided 4% significance level, under a 2-look group sequential design. Clinical trial information: NCT06203210 .

Preliminary safety, efficacy and molecular characterization of emavusertib (CA-4948) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) with FLT3 mutation (FLT3m).

6539 Background: AML is a heterogenous disease and exhibits a dynamic mutational landscape as the disease progresses. Internal tandem duplication (ITD) of FLT3 is considered an acquired late-event mutation and is associated with a poor prognosis in AML. Emavusertib is a potent oral inhibitor of both IRAK4 and FLT3, conferring potential dual efficacy advantages compared to other IRAK4 or FLT3 inhibitors as single agents. IRAK4 is upregulated during anti-FLT3- or other cytotoxic therapies, which drives a resistance pathway of early relapse and progression. Methods: The safety, clinical activity, and potential biomarkers of emavusertib in R/R AML and higher-risk myelodysplastic syndrome are being investigated in the ongoing open-label, Phase 1/2a TakeAim Leukemia trial (NCT04278768). Next generation sequencing (NGS) of 68 genes was performed on genomic DNA from bone marrow or peripheral blood mononuclear cells at baseline and on treatment. Here, we present preliminary safety, efficacy data and molecular characterization in a subset of enrolled AML patients who carried FLT3m at baseline and were treated with emavusertib monotherapy. Results: In this study, we treated 11 R/R AML patients with FLT3m at dose levels of 200-400 mg BID. The median number of prior anti-cancer therapies was 2 (range 1-6). 8 of 11 patients had prior exposure to FLT3 inhibitors. Treatment-related adverse events (TRAEs) Grade ≥ 3 were reported in 2 of 11 (18%) patients. All responders were dosed at the Recommended Phase 2 Dose (RP2D) of 300 mg BID and with < 3 lines of prior therapy. In addition, responders demonstrated more than 90% bone marrow blast reduction compared to baseline. The most common co-mutations in this subset of patients included RUNX1, NRAS, and TET2. Emavusertib treatment significantly decreased the variant allele frequency of these mutations. FLT3-ITD levels were decreased or became undetectable in responders. Additional corelative analysis between bone marrow blast counts and mutation status indicates that AML patients with FLT3m demonstrated increased bone marrow blast reductions (P≤0.05) on emavusertib treatment, when compared to FLT3 WT AML patients. Conclusions: Emavusertib has a favorable safety and tolerability profile in pretreated AML patients with FLT3m and demonstrated monotherapy anti-cancer activity in patients with FLT3m, including patients who have progressed on prior FLT3 inhibitors. Mutational profiles are suggestive of disease-modifying activity of emavusertib. We will present updated safety and efficacy data, including data for patients who proceeded to stem cell transplant. Enrollment in this ongoing trial is continuing at RP2D in patients with < 3 lines of prior anti-cancer therapies. Clinical trial information: NCT04278768 .

Efficacy and safety of erdafitinib in adults with NSCLC and prespecified fibroblast growth factor receptor alterations in the phase 2 open-label, single-arm RAGNAR trial.

8515 Background: Erdafitinib is an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved in the US for treatment of locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3 alterations, as determined by FDA-approved companion diagnostic test, who have progressed during or after ≥1 line of prior systemic therapy. Primary analysis results from the RAGNAR study demonstrated tumor agnostic efficacy in patients with advanced solid tumors with predefined FGFR alterations after failure of standard therapies (Pant 2023). Here we report results on patients with non-small-cell lung cancer (NSCLC) in the RAGNAR study. Methods: Patients with advanced or metastatic squamous or non-squamous NSCLC with prespecified FGFR1-4 alterations (mutations/fusions) and with documented disease progression after exhausting standard therapies were included. Patients with other targetable alterations (eg, EGFR, ALK, ROS1) were excluded. Patients received oral erdafitinib until disease progression or intolerable toxicity. The primary end point was objective response rate by independent review committee. Secondary endpoints include duration of response, disease control rate, progression-free survival, overall survival, and safety. Results: At data cutoff (median survival follow-up of 23.7 months), 23 patients with NSCLC received erdafitinib. Median age was 63 years (range 50-79); 22 (96%) had metastases. Patients had a median of 2 prior lines of systemic therapies (range 1-7; 48% had 3+ prior lines); only 2 (9%) patients had responded to their prior line of therapy. Fourteen patients (61%) had squamous and 9 (39%) non-squamous histology; 13 patients (57%) had FGFRfusions and 10 (43%) had FGFR mutations. Three patients had CDKN2Aand 3 patients had PIK3CA co-alterations. Objective response rate by independent review committee was 26% (95% CI 10-48); disease control rate was 74% (95% CI 52-90). Median time to onset of response was 1.5 months. Responses were observed in 21% (3/14) of patients with squamous; 33% (3/9) with non-squamous histology, 29% (2/7) of patients with FGFR2, 25% (4/16) with FGFR3alterations, and in 20% (2/10) of patients with FGFR mutations and 31% (4/13) with fusions. Median duration of response, progression-free survival and overall survival were 4.6 months, 4.1 months, and 10.5 months, respectively. Most common adverse events (AEs) were diarrhea (65%), stomatitis (61%), dry mouth (44%), hyperphosphatemia (65%), dry skin (30%), and fatigue (22%); 6 (26%) had serious AEs; 2 (9%) discontinued erdafitinib due to AEs. No treatment-related deaths were observed. Conclusions: Erdafitinib demonstrated clinically meaningful activity in pre-treated patients with NSCLC and pre-specified FGFR alterations. Safety data were consistent with erdafitinib safety profile. Clinical trial information: NCT04083976 .

Ambulatory teclistamab administration in patients with relapsed/refractory multiple myeloma.

11146 Background: Teclistamab (Tec) is the first B-Cell Maturation antigen (BCMA)xCD3 bispecific antibody FDA approved for the treatment of relapsed or refractory multiple myeloma (RRMM) in patients who have received ≥4 prior lines of therapy. The phase 1-2 MajesTec-1 study raised concerns for cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS). 48-hour inpatient observation is recommended for step-up dosing, which imposes financial and logistical burdens. We report our institutional experience with ambulatory Tec administration. Methods: Our inpatient/outpatient (IPOP) hybrid nursing unit is staffed with specialized nurses, advanced practice providers, and attending physicians. Our patients treated in IPOP must live within 1 hour of the hospital and have a 24-hour caregiver. Patients were treated with the recommended step-up dosing schedule. CRS grading and ICE scoring were performed daily. Both CRS and ICANS were graded according to the ASTCT grading systems. We collected toxicities until the second full treatment dose, at which point hospitalization is no longer recommended. Results: In total, 25 patients were treated with Tec between January 2023 to December 2023. The median age was 70 years old (range 59-89), with a median of 6 prior lines of therapy. One patient was dialysis dependent prior to starting Tec. All patients were triple class refractory. Thirteen patients (52%) received prior bone marrow transplant. One (4%) patient received prior anti-BCMA CAR-T therapy. Seventeen patients (68%) required admission during the Tec ramp-up period. CRS was observed in 15 (60 %) patients, all of which were grade I/II events. Fourteen of these patients were hospitalized for CRS. They were admitted for median number of 2 hospital days (range 1-6). Tocilizumab was administered for Grade 2 CRS in 3 patients (12%). ICANS was reported in 4 (16%) patients. Two of those patients developed Grade 2 ICANS which completely resolved with dexamethasone. The median number of admitted hospital days for these patients was 3 days (range 2-49). Neutropenia with ANC < 500 was seen in only 1 (4%) patient. Grade 3/4 infections were seen in 3 (12%) patients during the ramp-up period. Conclusions: Tec administration through an inpatient/outpatient hybrid model is safe and feasible. CRS was common but low grade and short lived. ICANS was observed, but remained low grade and may be attributable to our older patient population. As our center gained experience with the Tec management, we noticed lower rates of admission for low grade CRS. Lower incidences of infections and neutropenia demonstrate that these complications emerge in the months after starting therapy. Future studies will help identify patients who are higher risk for CRS and ICANS during ramp-up treatment and may pave the way for prophylactic interventions and outpatient administration.

A three-arm randomized phase II study of dostarlimab alone or with bevacizumab versus nonplatinum chemotherapy in recurrent gynecological clear cell carcinoma: DOVE (APGOT-OV7/ENGOT-ov80 study).

TPS5627 Background: Recurrent gynecological clear cell carcinoma (rGCCC) is known for low objective response rates to chemotherapy. Prior preclinical and clinical data suggests potential synergy of immune checkpoint inhibitor adding bev in rGCCC. Dostarlimab, a humanized monoclonal antibody targeting PD-1, combined with the anti-angiogenic bevacizumab, presents a novel therapeutic approach. The aim of the present study is to investigate the efficacy of dostarlimab +/- bevacizumab in rGCCC. Methods: DOVE is a global, multicenter, international, open-label, randomized phase 2 study of dostarlimab +/- bevacizumab with standard chemotherapy in patients with rGCCC. It enrolls 198 patients with rGCCC, assigning them to one of three groups in a 1:1:1 ratio: Group A (dostarlimab monotherapy), Group B (dostarlimab + bevacizumab), Group C: investigator’s choice chemotherapy. Patients with PD on Group A or Group C were allowed to crossover to Group B. Stratification factors are prior bevacizumab use, prior lines of therapy (1 vs. >1), and primary site (ovarian vs. non-ovarian). Key inclusion criteria are histologically proven confirmed recurrent or persistent clear cell carcinoma of the ovary, endometrium, cervix, vagina and vulva, up to 5 prior lines of therapies, disease progression within 12 months after platinum-based chemotherapy, and measurable disease. Key exclusion criteria are prior treatment with an anti PD-1, anti PD-L1, or anti PD-L2 agent. The primary endpoint is progression-free survival by investigator. The secondary endpoints include ORR, DCB, DCR, PFS2, OS, and toxicity. Exploratory objectives include immune biomarker. The study, commencing in Jan 2024, is registered with Clinicaltrials.gov (NCT06023862). Clinical trial information: NCT06023862 .

Co-occurrence of ESR1 and PIK3CA mutations in HR+/HER2- metastatic breast cancer: Incidence and outcomes with targeted therapy.

e13097 Background: ESR1 and PIK3CA mutations inform the use of targeted agents such as alpelisib (A), elacestrant (E), and capivasertib in patients (pts) with HR+/HER2- metastatic breast cancer (mBC). These mutations predict a worse prognosis and shorter response to endocrine therapy (ET). The prevalence of PIK3CA and ESR1 mutations detected via circulating tumor DNA (ctDNA) in mBC is about 35% and 33%, respectively, and the co-occurrence rate is 10-15%. Treatment outcomes with these targeted agents in pts with both mutations can inform sequencing decisions. Methods: We retrospectively analyzed pts treated at Miami Cancer Institute with HR+/HER2- mBC who underwent ctDNA testing (performed by Guardant360) between March 2019 and Jan 2024. The rate of co-occurring pathogenic ESR1 and PIK3CA mutations on a single sample was quantified. We report pt demographics, disease characteristics, and real world outcomes on A + ET and E in the co-mutated cohort. Results: Of the 626 pts who underwent ctDNA testing, 31.6% (n=198) had at least one PIK3CA mutation and 23.8% (n=149) had at least one ESR1 mutation. Co-mutations in both ESR1 and PIK3CA were found in 10.4% (n=65). In the co-mutated cohort, median age was 63, 84.6% were post-menopausal, and 58.5% were Hispanic. Most pts received prior CDK4/6 inhibitor (90.7%). A + ET was administered to 27 pts (41.5%) with a median of 2 prior lines of therapy (range 1-8). In these pts, 33.3% (n=9) achieved stable disease, 25.9% (n=7) partial response, 14.8% (n=4) progression, and 18.5% (n=5) discontinued due to toxicity prior to re-staging. E was administered to 12 pts (18.5%) with a median of 4 prior lines of therapy (range 1-13), with 4 pts still on treatment. None achieved stable disease or objective response, 66.7% (n=8) developed progression of disease as best response, and 33.3% (n=4) currently remain on treatment pending response evaluation. In the co-mutated cohort, only 4 received both A + ET and E, (3 received A first, 1 received E first). Pts treated with A + ET only (n=23) had a median time to next treatment (mTTNT) of 120 days (range 5-566) and those who received E only (n=8) had a mTTNT of 86 days (range 13-106) (Chi square=4.289, df = 1, p<0.05). The 4 pts who received both therapies were excluded from this mTNNT analysis. Conclusions: The rate of ESR1 and PIK3CA co-mutation in this cohort was consistent with the reported literature. mTTNT was significantly longer with A + ET compared to E, but real world outcomes on E remain immature with one-third of pts still on E at the time of analysis. A limitation of this study was the small sample size. Further analyses are warranted to clarify the optimal sequencing of these targeted therapies such as A, E, and capivasertib in pts with co-mutations in ESR1 and PIK3CA.

Glofitamab monotherapy in patients with heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL): Updated analysis from a phase I/II study.

7008 Background: Glofitamab, a bispecific antibody with a novel 2:1 (CD20:CD3) format, engages and redirects T cells to eliminate malignant B cells. In a Phase I/II study (NCT03075696), fixed-duration glofitamab monotherapy showed high, durable complete responses (CR) and manageable safety in patients (pts) with heavily pretreated R/R MCL (Phillips et al. ASH 2022). We report updated efficacy and safety data for pts with R/R MCL. Methods: Pts received obinutuzumab pretreatment (Gpt; 1000mg or 2000mg) 7 days before their first glofitamab dose. Glofitamab step-up dosing was given on Cycle (C) 1 Day (D) 8 (2.5mg) and D15 (10mg), and target dose (16mg or 30mg) from C2D1 to C12 as a fixed-duration therapy. Efficacy endpoints were CR, overall response rate (ORR), duration of CR (DOCR), duration of response (DOR) and progression-free survival (PFS). Post-hoc PFS and overall survival (OS) landmark analyses were performed in pts with a CR at end of treatment (EOT). Results: As of Sept 4, 2023, 61 pts were enrolled; 60 received study treatment (1000mg Gpt, n=16; 2000mg Gpt, n=44). Median number of prior lines of therapy was 2 (range: 1–5); 73.3% were refractory to the last line of prior therapy. Median duration of glofitamab therapy was 7.4 months; median number of cycles was 12. Of the 31 pts (51.7%) who received prior Bruton’s tyrosine kinase inhibitor (BTKi) therapy, 29 (93.5%) were BTKi refractory; median number of prior lines of therapy was 3 (range: 1–5); 90.0% were refractory to the last line of prior therapy. At a median PFS follow-up of 17.2 months, ORR and CR rate were 85.0% and 78.3%, respectively. Median DOCR was 15.4 months; the majority of CRs (28/47; 59.6%) were ongoing at data cut-off. Of 19 pts with a CR, 9 had disease progression and 10 died (fatal adverse event [AE], n=8; COVID, n=7; septic shock, n=1). Estimated 12-month DOCR and DOR rates were 71.0% and 66.6%, respectively. Median PFS was 16.8 months. Landmark analyses indicated that most pts with a CR at EOT were alive and progression free 15 months post-EOT (OS rate, 72.7%; PFS rate, 59.2%). Observed efficacy data were consistent across both Gpt cohorts. In post-BTKi pts after a median PFS follow-up of 26.1 months, ORR and CR rate were 74.2% and 71.0%, respectively. Median DOCR was 12.6 months; median PFS was 8.6 months. No new safety signals were observed. Cytokine release syndrome (CRS) remained the most common AE (42/60, 70.0%; Grade 1/2, 58.3%) and was lower in the 2000mg (63.6%) vs the 1000mg (87.5%) Gpt cohort. Glofitamab monotherapy (2000mg Gpt) is currently under investigation in the Phase III GLOBRYTE study (NCT06084936). Conclusions: Fixed-duration glofitamab continues to demonstrate compelling response rates that are maintained beyond EOT, with long-term durability observed in heavily pretreated pts with R/R MCL, including pts with prior BTKi therapy. The safety profile was manageable and CRS mainly low grade. Clinical trial information: NCT03075696 .

Sequential use of PI3K/AKT/mTOR pathway inhibitors alpelisib and everolimus in patients with hormone receptor-positive (HR+) metastatic breast cancer.

1057 Background: Alpelisib (A), a PI3K inhibitor, is FDA-approved with fulvestrant for patients with PIK3CA-mutated HR+/HER2- MBC. Everolimus (E), an mTOR inhibitor, is FDA-approved with endocrine therapy (ET) regardless of PI3K/AKT/mTOR pathway mutation status. The efficacy and safety of sequential treatment with these pathway inhibitors is not well described. Methods: This single-center retrospective cohort study identified patients with HR+/HER2- MBC treated with both A and E sequentially, each in combination with ET, in either order from 2012-2023. We collected information on patient demographics, clinical and pathologic characteristics, treatment history, treatment adverse effects, and dates of disease progression (defined as radiographic or clinical progression leading to treatment change) from medical records. Patients treated first with E then A were categorized as Group 1 and those first with A then E as Group 2. Rates of prior CDK4/6i use were compared between groups with the chi-square test; differences in prior lines of therapy were assessed with the Wilcoxon rank sum test. Median PFS1 (PFS on 1st pathway inhibitor) and PFS2 (PFS on 2nd pathway inhibitor) were computed using the Kaplan-Meier method and the impact of prior treatment on PFS2 between groups was compared using Cox proportional hazards analysis. Results: 115 patients with HR+/HER2- MBC were included in this study. There were 62 (54%) patients in Group 1 and 53 (46%) patients in Group 2. Median prior lines of therapy in the metastatic setting for Group 1 was 4 (range 1-13) and for Group 2 was 3 (range 1-8; p=0.08). Median number of intervening therapies between E and A in Group 1 was 2 (range 0-8) and between A and E in Group 2 was 0 (range 0-4; p<0.001). 34/62 (55%) patients in Group 1 and 45/53 (85%) in Group 2 received prior CDK4/6i ( p<0.001). In Group 1, 49/62 (79%) of patients discontinued E for progression and 13 (21%) discontinued for toxicity. Median PFS1 was 9.2 months (95%CI 5.5-13.0) and PFS2 was 5.0 months (95%CI 4.6-7.9). In Group 2, 34/53 (64%) of patients discontinued A for progression and 19 (36%) discontinued for toxicity. Median PFS1 was 9.3 months (95%CI 7.0-14.0) and PFS2 was 3.5 months (95%CI 3.0-4.1). After adjusting for prior CDK4/6i use and prior lines of therapy (total and intervening), PFS2 was not significantly different between the groups. Genomic information will be included at the time of presentation. Conclusions: This is the largest retrospective study to-date of patients treated sequentially with PI3K/AKT/mTOR pathway inhibitors. PFS was longer with the 1st pathway inhibitor than with the 2nd regardless of sequence. This has implications for optimal integration of capivasertib, an AKT inhibitor, into HR+ MBC treatment. Prospective studies testing optimal sequencing are needed.

ATHENA: A phase 1/2 study of AZD5851, a chimeric antigen receptor (CAR) T-cell therapy directed against GPC3 in adult patients with advanced/recurrent hepatocellular carcinoma (HCC).

TPS2675 Background: Checkpoint inhibitor therapy is the standard first-line treatment for advanced/recurrent HCC, but there is a significant unmet therapeutic need for patients (pts) who progress after first-line treatment. Adoptive cellular immunotherapy may provide a novel treatment option. Glypican-3 (GPC3), a heparan sulfate proteoglycan, is overexpressed by tumor cells in HCC and virtually absent in healthy tissues, making it an ideal target for CAR-T therapy. AZD5851 is an autologous CAR-T product that expresses a CAR specific for GPC3 and a dominant negative (dn)TGFβRII as an armoring strategy. Expression of dnTGFβRII can block TGFβ signaling, protecting CAR T-cells from the immunosuppressive effects of this cytokine. Early clinical data with C-CAR031, a CAR-T product with the same GPC3-specific CAR and dnTGFβRII-armoring transgene as AZD5851, showed promising tolerability and antitumor activity in pts with HCC [1]. ATHENA (NCT06084884) is a first-in-human, single-arm, open-label, multicenter phase 1/2 study to evaluate the safety, tolerability, and antitumor activity of AZD5851 in pts with GPC3+ advanced/recurrent HCC, for whom ≥1 prior line of standard therapy failed or was not tolerable. Methods: Eligible pts are aged ≥18 years with histologically confirmed advanced/recurrent or metastatic and/or unresectable HCC, GPC3+ tumor sample as determined by immunohistochemistry, ≥1 prior line of standard systemic therapy, ≥1 measurable lesion per RECIST 1.1, Child-Pugh A, ECOG PS 0/1, and adequate organ and bone marrow function. Approximately 24 pts will be enrolled in Part A (Phase I, dose escalation) and 50 in Part B (Phase II dose expansion). Pts will undergo apheresis to collect peripheral blood mononuclear cells for AZD5851 production, after which they may receive approved bridging therapy for disease control. Upon successful generation of AZD5851 product, pts will undergo lymphodepletion before receiving a single dose of IV AZD5851. Subsequent follow-up is divided into 3 stages: Stage 1, active follow-up of all pts through 6 months post AZD5851 infusion; Stage 2, further evaluation of pts who have not progressed or started a new anticancer regimen during Stage 1; Stage 3, long-term follow-up for all pts who have received AZD5851. The primary endpoints are to assess the safety/tolerability of AZD5851 (both study parts), and to determine the recommended dose(s) of AZD5851 for expansion and phase 2 trials (Part A). Secondary endpoints include efficacy (objective response rate, best overall response, duration of response, disease control rate, durable response rate, time to response, progression-free survival, and overall survival) and pharmacokinetics. Exploratory endpoints include pharmacodynamic biomarkers and immunogenicity. Enrollment began Nov 2023. 1. Zhang et al. AACR 2023. Abstract CT097. Clinical trial information: NCT06084884 .

Telisotuzumab vedotin monotherapy in patients with previously treated c-Met–overexpressing non-squamous EGFR wildtype advanced NSCLC: Primary analysis of the LUMINOSITY trial.

103 Background: Approximately 25% of patients (pts) with non-squamous (NSQ) EGFR wildtype (WT) NSCLC have c-Met protein overexpression (Ansell et al. 2022 CRUK), which is associated with a poor prognosis (Liang, Wang. Onco Targets Ther. 2020). Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate comprising the mAb telisotuzumab and the microtubule polymerization inhibitor monomethyl auristatin E. The phase 2 LUMINOSITY trial (NCT03539536) aimed to identify the c-Met–overexpressing (OE) NSCLC population best suited to Teliso-V and expand selected group(s) for further evaluation of efficacy. We report on the primary analysis for pts with c-Met OE NSQ EGFRWT NSCLC. Methods: This phase 2, non-randomized, multicenter study enrolled pts with locally advanced/metastatic c-Met OE NSCLC, ≤2 prior lines of therapy (chemotherapy [CTx] + immunotherapy [IO] or sequential CTx + IO), and ≤1 line of chemotherapy. c-Met OE (Ventana MET [SP44] clinical trial assay [CTA]) was defined as ≥25% tumor cells with 3+ staining (high: ≥50% 3+; intermediate [int]: 25 to <50% 3+). Teliso-V was dosed at 1.9 mg/kg IV Q2W. Primary endpoint was overall response rate (ORR) by independent central review per RECIST v1.1. Results: 172 pts with NSQ EGFR WT NSCLC received ≥1 dose of Teliso-V and comprised the safety population; 161 (c-Met high, 78; c-Met int, 83) were included in baseline and efficacy analyses. Median age was 64 yrs (range 33–83), 69% were male, and 70% had ECOG PS 1. 97.5% had prior platinum and 82.0% had prior immune checkpoint inhibitor. Efficacy data are presented in Table below. ORR was 34.6% (c-Met high), 22.9% (c-Met int), 28.6% (overall). Median DOR was 9.0 mo (c-Met high), 7.2 mo (c-Met int), 8.3 mo (overall). Most common any-grade treatment-related AEs (TRAEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%). Grade 5 TRAEs occurred in 2 pts (interstitial lung disease, respiratory failure). Conclusions: Teliso-V has shown compelling and durable responses in pts with c-Met OE NSQ EGFR WT NSCLC, especially in pts with c-Met high. Teliso-V had an acceptable safety profile that was clinically manageable, which is consistent with previous data. Clinical trial information: NCT03539536 . [Table: see text]

Longer-term follow-up of patients (pts) receiving prophylactic tocilizumab (toci) for the reduction of cytokine release syndrome (CRS) in the phase 1/2 MajesTEC-1 study of teclistamab in relapsed/refractory multiple myeloma (RRMM).

7517 Background: Emerging data suggest that administering toci prior to bispecific antibodies reduces the incidence of CRS, which may support outpatient therapy initiation. We previously showed that the incidence of CRS with teclistamab, the first approved BCMA×CD3 bispecific antibody with weight-based dosing for the treatment of pts with triple-class exposed RRMM, was reduced from 72% in the overall MajesTEC-1 study population to 26% in a cohort receiving a single dose of toci before the first teclistamab step-up dose. Here, we present an updated analysis with longer-term follow-up. Methods: Pts with triple-class exposed RRMM received subcutaneous teclistamab 1.5 mg/kg weekly in a prospective exploratory cohort or at a comparable fixed dose, following 2 step-up doses. Toci 8 mg/kg was given intravenously ≤4 hours before the first teclistamab step-up dose. CRS was graded per Lee et al ( Blood 2014;124:188-95) and managed per the study protocol. Results: This analysis included 24 pts with median follow-up 8.1 months (range, 0.9–13.2). Median age was 72 years (range, 50–82); 100% had ECOG PS score ≤1; 96% had International Staging System stage I/II; 74% had standard-risk cytogenetics; 21% had extramedullary plasmacytomas; 33% had ≥30% bone marrow plasma cells (biopsy or aspirate). Pts had a median of 4 prior lines of therapy (range, 2–9); 58% were triple-class refractory. CRS occurred in 6 pts (25%; 2 grade 1, 4 grade 2, no grade ≥3); 3 pts each had 1 recurrent CRS event. Median time to CRS onset was 2 days (range, 1–3); median duration was 2 days (range, 2–4). CRS was managed with additional toci in 5/6 pts and steroids in 1/6; all CRS events resolved and none led to teclistamab discontinuation. Most common adverse events (AEs; any grade/grade 3/4) were infections (79%/25%), neutropenia (63%/63%), and anemia (58%/25%); 5 pts had a neurotoxicity AE (grade 1 dizziness; grade 1 headache; grade 1 insomnia; grade 2 headache; grade 2 immune effector cell-associated neurotoxicity syndrome). Overall response rate (n=22) was 73% (59% very good partial response or better). Timing of interleukin (IL)-6 induction in the prophylactic toci cohort was consistent with the phase 1 MajesTEC-1 population, with higher IL-6 levels as observed in other studies of IL-6 receptor-blocking antibodies. Conclusions: Prophylactic toci reduced the incidence of CRS with teclistamab, with a 65% relative reduction vs the overall MajesTEC-1 population (grade 1, 8% vs 50%; grade 2, 17% vs 21%). No new safety signals or impact on response to teclistamab was observed with longer follow-up. Prophylactic toci may be a useful measure to consider when selecting pts for outpatient administration of teclistamab in the future. This approach is being evaluated in the phase 2, multicenter, prospective OPTec study (NCT05972135). Clinical trial information: NCT03145181 / NCT04557098 .

A phase 1 study of fianlimab (anti–LAG-3) in combination with cemiplimab (anti–PD-1) in patients with advanced HNSCC.

6038 Background: Concurrent blockade of LAG-3 may enhance efficacy of anti–PD-1 therapies. We present safety and clinical activity data from a Phase 1 study in patients (pts) with head and neck squamous cell carcinomas (HNSCC) treated with anti–LAG-3 (fianlimab) + anti–PD-1 (cemiplimab). Methods: Two expansion cohorts of adult pts with recurrent and/or metastatic HNSCC with no curative options who were anti–PD-1/PD-L1-naïve (cohort 11) or anti–PD-1/L1-experienced with most recent dose within 3 months (mos) prior to screening (cohort 12) were enrolled. All pts received fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks (wks) for up to 24 mos. Tumor measurements were performed every 6 wks for 24 wks, then every 9 wks. Results: 15 pts each in cohort 11 and 12 (total N=30; median age: 69 years) were enrolled and treated with fianlimab + cemiplimab as of 04 Oct 2023 data cutoff.For cohorts 11 and 12 respectively, 80% and 87% of pts were male, and 53% and 80% were White. All pts had prior cancer-related systemic therapy. 33% (5/15) and 87% (13/15) of pts in cohorts 11 and 12 had ≥2 lines of prior therapies, respectively. For cohorts 11 and 12, median treatment duration was 12 wks (mean: 41 wks) and 13 wks (mean: 24 wks), and median follow-up was 12 mos and 10 mos, respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 47% of pts each in cohorts 11 and 12. Serious TEAEs occurred in 13% and 20% of pts in cohorts 11 and 12, respectively. Treatment-related TEAEs (TRAEs) were reported in 67% of pts in cohorts 11 and 53% of pts in cohort 12. The most common TRAEs (any grade) were hypothyroidism (33%) in cohort 11; and fatigue (20%) and pneumonitis (20%) in cohort 12. Grade ≥3 TRAEs occurred in 7% of pts in cohorts 11 and 13% of pts in cohorts 12. Treatment-related immune-related AEs were reported in 47% and 40% of pts in cohorts 11 and 12, respectively. Treatment was discontinued due to any TEAE in 2 pts in cohort 12. In cohort 12, there was one death due to grade 5 respiratory failure attributable to aspiration pneumonia. RECIST 1.1-based investigator-assessed objective response rate (ORR) was 33% (5 partial responses [PRs]) in cohort 11 and 7% (1 PR) in cohort 12. The disease control rate (DCR) was 47% and 67% in cohorts 11 and 12, respectively. Kaplan–Meier estimation of median progression-free survival was 2 mos (95% CI, 1–14) in cohort 11 and 4 mos (95% CI, 1–7) in cohort 12 pts. Duration of responses were 17, 10, 20, 22, and 20 mos in 5 responders in cohort 11; and 32 mos in 1 responder in cohort 12. Estimated event-free probability at 12 month was 33% (95% CI, 12–56) in cohort 11 and 16% (95% CI, 3–40) in cohort 12 pts. Conclusions: Fianlimab + cemiplimab in pts with HNSCC showed signs of clinical activity with durable responses among pts with anti–PD-1/PD-L1-naïve (cohort 11) and anti–PD-1/L1-experienced (cohort 12), with an acceptable safety profile which warrants further investigation. Clinical trial information: NCT03005782 .

Results of a phase 2 study of evorpacept (E, ALX148), cetuximab (C), and pembrolizumab (P) in patients with refractory microsatellite stable metastatic colorectal cancer (MSS CRC).

3530 Background: Single-agent anti-PD-1/PD-L1 drugs are ineffective in MSS CRC. E is an engineered protein (high-affinity CD47-blocker fused to an inactive IgG Fc region), which blocks the CD47/SIRPα innate immune inhibitory phagocytosis checkpoint expressed on CRC and phagocytes, respectively. Preclinical evidence suggests ECP may be effective in MSS CRC. Methods: This phase 2, single-arm, two-stage, multicenter, investigator-initiated trial of E (15 or 10 mg/kg weekly at dose level [DL] 1 and -1, respectively), C (400 mg/m2 then 250 mg/m2 weekly), and P (200 mg every 3 weeks) in 21-day cycles enrolled patients with MSS CRC, regardless of tumor sidedness and RAS/BRAF status, refractory to ≥ 2 prior lines of therapy, including EGFR inhibitor if indicated (NCT05167409). All patients in both Stage 1 (safety run-in) and Stage 2 (expansion) received ECP until progression or unacceptable toxicity. The co-primary objectives were to determine the recommended dose (RD) of E with CP and objective response rate (ORR) by RECIST v1.1 (by one-sided exact test with α=0.05, H0 p ≤ 3% [historical controls], HA p ≥ 15%; power is 87% with N=48). Results: The safety-evaluable population included 16 patients, of whom 69% were male and median age 53 years. The primary tumor was in the right, left, and transverse colorectum in 31%, 31%, and 6% of patients, and was unknown in 31%. Mutations in KRAS, NRAS, and BRAF genes were present in 38%, 6%, and 0% of patients. The median number of prior lines of therapy was 3, including prior EGFR inhibitor in 44%. In Stage 1, 9 and 3 patients were enrolled at E DL1 and DL-1, respectively. E DL1 was established as the RD for Stage 2, in which 4 patients were enrolled. The most common any-grade treatment-emergent adverse events were headache (32%), fatigue (26%), anemia (21%), diarrhea (21%), dyspnea (16%), abdominal pain (16%), nausea/vomiting (16% each), and acneiform rash (16%). There were two on-study deaths assessed as related to all three study drugs (hemophagocytic lymphohistiocytosis and cytokine release syndrome; 1 each). While both are known associations with checkpoint inhibitors, other significant factors contributing to these event outcomes included cancer progression with high tumor burden in the former and patient decision to transition to comfort care in the latter. In the safety-evaluable population, ORR was 6.3% (1 ongoing partial response, 95% confidence interval [CI] 0.2-30.2%), disease control rate was 12.5% (95% CI 1.6-38.4%), median progression-free survival was 2.6 months (mo; 95% CI 2.1-2.9 mo), and median overall survival was 10.9 mo (95% CI 3.3 mo-infinity). Formal hypothesis testing was not performed. Conclusions: Further dose optimization of ECP is needed to establish a RD in the refractory MSS CRC population. While initial activity was seen, at the DLs evaluated, criteria for study termination were met. Clinical trial information: NCT05167409 .

Pooled analysis by best confirmed response to trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ metastatic breast cancer (mBC) from DESTINY-Breast-01, -02, and -03.

1023 Background: DESTINY-Breast (DB)-01, -02, and -03 evaluated T-DXd in pts with HER2+ mBC who received ≥1 prior line of therapy. These studies showed confirmed objective response rates by independent central review (ICR; blinded for DB-02 and -03) of 62%, 70%, and 79% and complete response (CR) rates of 7%, 14%, and 21%, respectively, with T-DXd. We report a pooled analysis according to pts’ best confirmed response in DB-01, -02, or -03. Methods: Endpoints included best confirmed response per (blinded) ICR ([B]ICR) based on RECIST v1.1, duration of response (DoR), progression-free survival (PFS) by (B)ICR, overall survival (OS), and safety. Results: The median (range) duration of T-DXd treatment for pts with a CR, partial response (PR), or stable disease (SD)/progressive disease (PD) was 27.4 (4.5-45.1) mo, 14.0 (2.1-39.3) mo, or 6.2 (0.7-40.1) mo, respectively. Of 834 evaluable pts assigned to T-DXd in DB-01, -02, or -03, 125 (15.0%) had a CR, 477 (57.2%) had a PR, and 232 (27.8%) had SD/PD. Pts with CR had a median of 2 prior regimens (range, 1-11) in the metastatic setting, whereas pts with PR or SD/PD had a median of 3 prior regimens. As shown in the Table, pts with CR had more favorable PFS and OS outcomes vs pts with PR or SD/PD. The proportion of pts with drug-related, serious treatment-emergent adverse events (TEAEs) was numerically lower in pts with CR (8.0%) than those with PR (12.4%) or SD/PD (15.5%). Pts with CR also had numerically lower rates of drug-related TEAEs associated with T-DXd discontinuation (14.4% vs 17.8% or 16.8%) and adjudicated drug-related interstitial lung disease (ILD)/pneumonitis (8.8% [0 fatal] vs 15.1% [2 fatal] or 11.6% [5 fatal]) and longer median time to first ILD onset (461 days vs 211 or 125 days) vs pts with PR or SD/PD. Conclusions: Pts treated with T-DXd benefited from durable responses resulting in prolonged PFS and OS, especially those with a CR. Despite longer treatment duration in responders, safety remained generally manageable and did not result in a higher percentage of pts with TEAEs over time. These results further support the use of T-DXd across broad pt groups with HER2+ mBC. Clinical trial information: NCT03248492 , NCT03523585 , NCT03529110 . [Table: see text]

Efficacy, safety, and determination of RP2D of ABBV-383, a BCMA bispecific antibody, in patients with relapsed/refractory multiple myeloma (RRMM).

7531 Background: MM eventually becomes refractory to current treatments, and new therapeutic options with convenient dosing and improved safety are needed to enhance patient (pt) adherence, access, and outcomes. ABBV-383 is a distinctive next-generation BCMA x CD3 bispecific antibody composed of 2 high-affinity BCMA-binding domains, a low-affinity CD3-binding domain designed to reduce cytokine release syndrome (CRS) risk, and a silenced Fc tail for an extended half-life allowing convenient dosing. ABBV-383 monotherapy has shown promising activity in the ongoing first-in-human phase 1 trial in RRMM (Vij et al. Blood 2023;142[suppl 1]:3378). Here, safety and efficacy results are reported that support the RP2D of 60mg Q4W as the optimal therapeutic ABBV-383 monotherapy dose. Methods: This phase 1 open-label, dose-escalation/expansion trial (NCT03933735) enrolled pts with RRMM who received ≥3 prior lines of therapy with exposure to PI, IMiD, and anti-CD38 mAb. ABBV-383 regimens explored in the expansion phase included 60mg Q4W and 40 or 60mg Q3W. A modified dexamethasone premedication schedule and shortened CRS monitoring period were implemented in the 60mg Q4W cohort for cycle 1. IV ABBV-383 was administered as a flat dose with no step-up schedule. Treatment was continued until disease progression/unacceptable toxicity. Primary objectives were to assess safety, tolerability, PK, PD, and determine the RP2D. Efficacy evaluation was a secondary objective. TEAEs were assessed per CTCAE v5.0 and tumor response per IMWG 2016 criteria. Results: As of May 2023, 220 pts received ABBV-383 (median age: 68 yr [35–92]; median prior therapy lines: 5 [3‒23]). Median FU was 4.1 mo (0.8–5.2) at 60mg Q4W (n=21), 12.2 mo (1.3–34.4) at 40mg Q3W (n=55), and 24.2 mo (0.6–33.4) at 60mg Q3W (n=61). At 60mg Q4W, with the modified premedication regimen, CRS was reported in 43% of pts (38% G1, 5% G2), and ICANS in 5% of pts (G2). In Q3W cohorts, CRS was reported in 71% (40mg; 45% G1, 25% G2) and 70% (60mg; 51% G1, 18% G2, 2% G3) of pts. The incidence of G3/4 neutropenia, anemia, and thrombocytopenia was 14/24/10% at 60mg Q4W, 31/31/16% at 40mg Q3W, and 34/13/13% at 60mg Q3W. G3/4 infections occurred in 10/24/34% of pts at 60mg Q4W, 40mg and 60mg Q3W, respectively. ORR and ≥VGPR were 65/50% at 60mg Q4W, 64/53% at 40mg Q3W, and 60/52% at 60mg Q3W. Corresponding exposure-response (ER) analyses and correlative analyses further supported RP2D determination (separate abstract submissions). Conclusions: The optimal therapeutic dose of 60mg Q4W ABBV-383 monotherapy was selected on the basis of safety, efficacy, and ER analyses. The extended interval of Q4W, with a shortened CRS monitoring period in cycle 1 and no step-up dosing, will improve convenience and reduce the treatment burden for pts. ABBV-383 at 60mg Q4W will be investigated in the registrational phase 3 trial (NCT06158841) in RRMM. Clinical trial information: NCT03933735 .

Real world (RW) study of patients (pts) with relapsed or refractory (RR) blastic plasmacytoid dendritic cell neoplasm (BPDCN) treated with tagraxofusp (TAG).

e18533 Background: BPDCN is characterized by clonal expansion of plasmacytoid dendritic malignant cells that express CD123 and other markers. TAG, a CD123-directed therapy, is the only drug approved to treat BPDCN (US/EU). In August 2019, a European Named Patient Program (NPP) started to ensure pt access to TAG. To assess RW safety and efficacy of TAG treatment in RR BPDCN, a pt population with a very poor prognosis, we retrospectively analyzed data from pts enrolled in the NPP. Methods: Pts with RR BPDCN received TAG 12 mcg/kg qd on days 1-5 (or by day 10) of each 21-day cycle. The first TAG cycle was given inpatient with outpatient treatment allowed thereafter. Clinicians received training on capillary leak syndrome (CLS) monitoring and management guidelines. Primary endpoints were complete response (CR) after 2-3 cycles and CLS incidence and grade (G). Secondary endpoints included number of pts bridged to stem cell transplantation (SCT), progression-free survival (PFS), overall survival (OS), best overall response rate (ORR), duration of response (DOR), and safety. Results: Of 18 pts with RR BPDCN (median age 66 y [29–83]; 89% male), 67% had received 1 prior line of therapy and 28% 2 prior lines. At initial diagnosis, pts had disease involvement in bone marrow (89%), skin (67%), and lymph nodes (61%). Median time from initial diagnosis to TAG was 7.4 mo (1–27). At a median follow-up of 8 mo, pts received a median of 2 (1–5) TAG cycles. In 15 pts with ≥1 tumor assessment, the ORR was 67% (40% CR and 27% partial response [PR]) with a median DOR of 5 mo (95% CI, 3.0–not estimable [NE]). All 18 pts had a median PFS of 4.3 mo (95% CI, 1.4–12.9) and median OS of 8.6 mo (95% CI, 3.6–NE). In 15 pts with ≥1 tumor assessment, 6 (40%) pts were bridged to SCT and had durable posttransplant responses (CR 83%; PR 17%) with median DOR, PFS, and OS not reached. CLS was mostly mild to moderate in severity; 61% of pts had CLS in cycle 1 and only 1 pt had an event in cycle 2. The median time to CLS resolution was 4 days. Other than CLS, TAG-related nonhematologic G3-4 adverse events (AEs) and serious AEs (SAEs) occurred in 44% of pts, all during cycle 1, with hepatic cytolysis, pneumonia and tumor lysis syndrome reported in 2 (11%) pts each. Grade 3-4 thrombocytopenia and pancytopenia were reported in 2 (11%) pts each. Median time to resolution was 5 days for the nonhematologic G3-4 AEs/SAEs and 18 days for thrombocytopenia. Two (11%) pts had G3-4/SAE infections. There were no treatment-related deaths. Conclusions: TAG induced fast and durable responses, and a high response rate, in RR BPDCN pts, with prolonged survival in a poor prognosis population, where historic treatments show limited efficacy. There were no new safety signals. With proper selection, monitoring, and directed intervention, CLS is manageable, usually mild, limited to the first cycle, and does not recur. These RW results support the use of TAG in pts with RR BPDCN.

Efficacy and safety of sigvotatug vedotin, an investigational ADC, in NSCLC: Updated phase 1 results (SGNB6A-001).

8521 Background: Integrin beta-6 (IB6), a tumor-associated membrane protein, plays an important role in pathogenesis and invasiveness and its expression correlates with poor outcomes. Sigvotatug vedotin (SV), formerly called SGN-B6A, is an IB6-directed ADC with encouraging activity in NSCLC in the Ph 1 study SGNB6A-001 (NCT04389632) (Hollebecque 2023). Here, we report updated efficacy and safety of SV in NSCLC. Methods: SGNB6A-001 is an open-label, multicenter, Ph 1 study evaluating the safety, pharmacokinetics (PK), and antitumor activity (cORR, DOR, and PFS per RECIST v1.1, and OS) of SV in patients (pts) with advanced solid tumors. Multiple dose regimens were explored during dose escalation (Part A). Dose expansion (Part B) is ongoing with selected regimens in various tumors including NSCLC. Parts C and D will evaluate SV in combination with pembrolizumab in NSCLC and HNSCC. Eligible pts had no therapeutic options (Part A) or had received platinum-based and anti-PD-(L)1 therapy unless contraindicated (Part B) and were dosed with the SV expansion regimens on D1 and D8 in a 21-day cycle (2Q3W; 1.2/1.25 mg/kg total body weight [TBW]) or D1 and D15 in a 28-day cycle (2Q4W; 1.5 mg/kg TBW, 1.8 mg/kg adjusted ideal body weight [AiBW]). Results: As of 01-Dec-2023, 306 pts had received SV; 113 pts with NSCLC received expansion regimens in Parts A and B. Prior lines of therapy and efficacy data for all pts with NSCLC and select subgroups are summarized in the table; cORR was 19.5% (95% CI, 12.6-28.0) in all pts with NSCLC and 32.5% (95% CI, 18.6-49.1) in pts with non-squamous (non-Sq)/taxane-naive NSCLC. Additional time-to-event data will be presented. Rates of TEAEs, ≥G3 TEAEs, SAEs, and TEAEs leading to discontinuation were 98.2%, 46.0%, 33.6%, and 13.3% in pts with NSCLC, and were consistent in all treated pts. The most common ≥G3 TEAEs in pts with NSCLC were dyspnea (9.7%), fatigue (7.1%), and neutropenia (5.3%). One pt with NSCLC had a treatment-related death (pneumonitis). PK variability across weight groups was lowest with 1.8 mg/kg AiBW 2Q4W. Conclusions: SV continues to demonstrate encouraging antitumor activity and a manageable safety profile in pts with NSCLC. Data at 1.8 mg/kg AiBW 2Q4W support initiation of the Ph 3 SGNB6A-002 study in 2/3L NSCLC (NCT06012435) and combination with pembrolizumab in earlier settings. Clinical trial information: NCT04389632 . [Table: see text]