Citations

Abstract Objective The validity of progression-free survival (PFS) as a surrogate for overall survival (OS) in the antibody-drug conjugate (ADCs) era remains uncertain. We evaluated the association between treatment effects on PFS and OS in randomized trials of ADCs for metastatic breast cancer (mBC) and explored the surrogate threshold effect (STE). Methods PubMed, Embase, Cochrane, and ClinicalTrials.gov were searched for published randomized controlled phase II–IV trials evaluating ADCs in mBC and reporting hazard ratios (HRs) for both PFS and OS. A meta-epidemiological approach was used. The primary metric was the ratio of hazard ratios (rHR = HR_PFS/ HR_OS), with rHR < 1 indicating a larger effect on PFS. Trial-level associations were assessed using weighted linear regression (R²) and Spearman’s correlation. Results Twenty-one trials (n = 21; 18 phase III) evaluating nine ADCs were included. The pooled rHR was 0.79 (95% CI, 0.73–0.86), indicating a larger relative effect on PFS than OS. Numerically, the largest discrepancies were observed in triple-negative disease (rHR 0.72) and trials allowing crossover (rHR 0.71). Concordant statistical significance between endpoints occurred in 76% of the trials, whereas 24% showed a significant PFS benefit without OS improvement. The trial-level association between PFS and OS was moderate (R² = 0.62; ρ = 0.67). Conclusion Treatment effects on PFS consistently exceeded those on OS, although effect directions were highly concordant between endpoints. These findings provide an exploratory framework to contextualize the relationship between PFS and OS in ADC trials, requiring further validation in diverse clinical settings.

Abstract Introduction Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen (ER), progesterone (PR), and HER2 expression. It accounts for ∼15% of breast cancers and is more common in Black women, younger patients, and those with BRCA1 mutations. TNBC carries a poor prognosis with 5-year survival rates of 92% (localized), 66.8% (regional), and 14.3% (metastatic). Patients with high-risk of recurrence can be treated with different adjuvant therapies based on results of 3 trials (capecitabine, pembrolizumab, olaparib), but data on adverse events (AE) on their combination is limited.High-risk, stage II-III TNBC is treated with curative intent using neoadjuvant chemotherapy with pembrolizumab, followed by surgery and radiation. Pembrolizumab, an anti-PD-1 checkpoint inhibitor, was FDA-approved in 2021 based on KEYNOTE-522. This phase III trial showed that pembrolizumab plus chemotherapy significantly improved pathologic complete response (pCR) and event-free survival (EFS). 3-year EFS was 84.5% vs. 76.8% with placebo (HR 0.63); 5-year follow-up confirmed sustained benefit, with OS of 86.6%. Patients achieving pCR had better outcomes, while those with residual disease remained at high risk for recurrence, justifying further adjuvant therapy.In KEYNOTE-522, grade ≥3 treatment-related (AEs occurred in 77.1% receiving pembrolizumab-chemotherapy vs. 73.3% with placebo-chemotherapy. Pembrolizumab was linked to more serious AEs (34.1% vs. 20.1%) and higher discontinuation rates (23.3% vs. 12.3%). Before pembrolizumab, capecitabine was standard of care for TNBC with residual disease, based on the CREATE-X trial (HR 0.52 for OS benefit). Common AEs included hand-foot syndrome, fatigue, and liver enzyme elevation. Notably, KEYNOTE-522 excluded adjuvant capecitabine, and CREATE-X predated the use of pembrolizumab. Olaparib, a PARP inhibitor, was FDA-approved in 2022 for high-risk early TNBC with germline BRCA mutations, based on OlympiA. It improved invasive disease-free and OS. Grade ≥3 AEs included anemia, neutropenia, and fatigue. OlympiA did not include pembrolizumab or capecitabine, limiting insight into optimal sequencing or combination. Currently, no trials compare pembrolizumab, capecitabine, or olaparib directly, nor do they guide how to sequence or combine these therapies. Despite NCCN guidelines allowing combined/sequential use in high-risk patients, real-world safety and outcome data are lacking. This study aims to evaluate and compare the safety and effectiveness of capecitabine, olaparib, pembrolizumab, and their combinations. We will describe AE rates, onset, discontinuation, and dose modifications to inform clinical management and help reduce early termination of effective therapies. Methods We conducted a retrospective observational study across all Mayo Clinic sites. Eligible patients were ≥18 years with early-stage TNBC who initiated adjuvant therapy with capecitabine, pembrolizumab, olaparib, or combinations (capecitabine + pembrolizumab or olaparib + pembrolizumab) from October 2018 to September 2024. Patients with metastatic disease, other active malignancies, or receiving concurrent investigational therapy were excluded. The primary outcomes were incidence and timing of treatment-related AEs. Secondary outcomes included time to AE resolution, immune-related AEs, treatment interruptions/modifications, early discontinuation, and EFS. Time-to-event data will be analyzed using Kaplan-Meier and Cox proportional hazards models. Subgroup analyses by age, DPYD status, regimen, and dosing will be conducted. Data was abstracted from electronic health records and managed using REDCap. Results Data collection is completed. Final analyses are being conducted, and results will be presented at SABCS 2025. Citation Format: R. Garza-Morales, F. Raheem, D. Alton, S. Sharma, B. Murad, W. Harris, E. Terwilliger, F. Batalini. Analysis of Adverse Events and Outcomes of Adjuvant Therapies in TNBC as Monotherapy and Combination: Pembrolizumab, Capecitabine, and Olaparib [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-10-06.

ABSTRACT Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, accounting for 90%–95% of all thyroid cancers worldwide. For many years, treatment options for patients with locally advanced or metastatic radioiodine refractory disease were limited. Advances in understanding oncogenic and angiogenic signaling pathways, such as vascular endothelial growth factor receptors, fibroblast growth factor receptors, platelet derived growth factor receptor, rearranged during transfection ( RET) , and BRAF have led to the development of targeted therapies that have transformed management over the past two decades. Multikinase inhibitors such as lenvatinib, sorafenib, vandetanib, and cabozantinib have demonstrated clinical efficacy in randomized clinical trials. Most recently, mutation-specific kinase inhibitors such as selpercatinib for RET -fusion positive cancers, and the combination of dabrafenib with trametinib for BRAF V600E -mutant disease, have been approved and further expanded treatment options for these patients. In this review, we summarize the current evidence on Food and Drug Administration-approved targeted therapies for metastatic thyroid cancer and discuss their clinical impact.

Abstract Introduction: CD20xCD3 bispecific antibodies (BsAb) have been approved for use in relapsed/refractory (RR) large B-Cell lymphomas (LBCLs) with manageable toxicities. The main adverse events of clinical interest are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The risk factors for CRS and ICANS are not well understood. Knowledge of variables that contribute to increased risk may help clinicians identify and tailor management for high-risk patients (pts) and increase the comfort level for providers using these therapies in community practices. Methods: We performed a multicenter retrospective study at 21 US centers evaluating pts with RR LBCLs receiving commercially available epcoritamab (epco) or glofitamab (glofit) between 2023 and 2025. We obtained baseline characteristics, safety and efficacy outcomes. Univariate analysis was performed to identify associations between CRS, ICANS, and clinical variables of interest. Results: As of May 31, 2025, a total of 312 pts with RR LBCLs were treated with BsAb, Epco n=193 (62%), Glofit n= 119 (38%); median age 68; 63% male; 70% ECOG PS 0-1. Most common histologic type was diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) (n=239, 84%) followed by high-grade B-cell lymphoma (HGBL) (n=46, 16%). 179 pts (57%) were previously treated with chimeric antigen receptor T-cell (CAR-T) therapy, with 47% receiving CAR-T <6 months (mo) prior to BsAb. Among pts with prior CAR-T, CRS with CAR-T therapy of any grade occurred in 63%, with 26% ≥ grade 2. ICANS of any grade (G) occurred in 25% of pts (9.4% ≥ G3). Overall and complete response (ORR and CR) rates to BsAb were 51% and 29%, respectively. With a median follow up of 5 mo, median progression-free and overall survival (PFS and OS) were 2.3 and 7.3 mo, respectively. With BsAb treatment, CRS of any grade occurred in 117 (39%) patients: 24% G1, 8.7% G2, 4% G3, 1% G4 and 1% G5. The max grade CRS occurred most frequently after the third dose of epco (35%) and the first dose of glofit (23%). CRS was managed with additional steroids in 24% of pts and tocilizumab in 22%. 13% of pts experienced ICANS: 5.8% G1, 3.4% G2, 2% G3, 1% G4 and 0.3% G5. Factors that increased the risk for any grade CRS included: bulky disease ≥ 7.5 cm at time of BsAb treatment (OR 2.04, 95% CI 1.17 – 3.55, p = 0.012), elevated LDH (OR 2.56, 95% CI 1.45– 4.76, p = 0.002) and treatment with epco compared to glofit (OR 1.69, 95% CI 1.04- 2.77, p = 0.036). As G ≥2 CRS generally requires inpatient monitoring and management, we next compared the risk factors between pts with no CRS or G1 CRS and G ≥2 CRS. Factors associated with increased risk for high grade CRS included: bone marrow involvement by lymphoma (OR 3.47, 95% CI 0.97 – 11.3, p = 0.043), platelet count ≤ 75 (OR 2.46, 95% CI 1.21 – 4.87, p = 0.011), ≥ 2 extra nodal sites (OR 2.04, 95% CI 1.07 – 3.97, p = 0.032) and ≥G2 CRS with prior CAR-T (OR 3.35, 95% CI 1.13 – 9.97, p = 0.027). Factors that increased the risk for ICANS included: bulky disease (OR 2.67, 95% CI 1.28 – 5.49, p = 0.008), elevated Cr ≥ 1.5x ULN (OR 3.79, 95% CI 1.25 – 10.4, p = 0.012), elevated AST/ALT ≥ 3x ULN (OR 4.65, 95% CI 0.92 – 19.9, p = 0.042), low albumin (OR 2.85, 95% CI 1.49 - 5.5, p = 0.002), and co-occurrence of CRS with BsAb (OR 9.1, 95% CI 3.85- 25, p < 0.001). No other clinical variables including older age, histologic subtype, ECOG PS, B symptoms, IPI score, cell of origin or histologic subtype, baseline labs such as ALC, CRP, fibrinogen or D-dimer were significantly associated with CRS or ICANS risk. There was no difference in ORR or CR rates in patients who experienced CRS or ICANS. Conclusions: Our analysis of pts treated with commercial BsAb for LBCL shows an increased risk for CRS and ICANs based on clinical variables that are routinely obtained at baseline including tumor bulk, sites of disease, laboratory parameters, and history of prior CRS with CAR-T therapy. Differences in baseline populations receiving epco and glofit treatments in this real-world analysis have been previously reported (Brooks et al, Blood 2025) and the comparative risk for CRS between these treatments remains unclear. Future plans including multivariable analysis may allow for development of a predictive model to identify pts at high risk of CRS and ICANS with BsAb treatment, potentially leading to prospective clinical trials evaluating prophylactic interventions for high-risk pts.

Abstract Introduction: Epcoritamab (epco) and glofitamab (glofit) are bispecific antibodies (BsAbs) approved for the treatment of patients (pts) with multiply relapsed or refractory (r/r) large B-cell lymphoma (LBCL). Though response rates are relatively high, most patients (pts) eventually experience progression of disease (POD). We sought to investigate the treatment patterns and clinical outcomes following POD post-BsAb for r/r LBCL Pts, as this has not previously been described. Methods: We performed a multicenter retrospective study including 21 US centers evaluating pts with r/r LBCL receiving commercially available epco or glofit between 2023 and 2025. Baseline characteristics and outcomes were extracted from medical records. Efficacy and survival outcomes were assessed by site investigators and included overall response rate (ORR), complete and partial response (CR, PR) rates, progression-free survival (PFS) and overall survival (OS), analyzed using the Kaplan Meier method. Results: As of May 15, 2025, a total of 312 pts with r/r LBCLs were treated with BsAb, of whom a total of 168 (53.8%) pts experienced POD [104 of 193 (53.8%) treated with prior epco and 64 of 119 (53.8%) treated with prior glofit]. Pts with POD had a median age at BsAb start of 67 years (interquartile range [IQR] 58-76), most were male (68.4%), and the most common histology was diffuse large B-cell lymphoma not otherwise specified (n=122 [71.8%]). Sixty-seven of 168 pts (39.9%) with POD after BsAb had experienced primary refractory disease defined as failure to achieve PR or CR to frontline therapy. A total of 102 (60.7%) pts with POD to BsAb had received chimeric antigen receptor (CAR) T-cell therapy prior to BsAbs, with 33.3% of these pts being refractory to CAR T and 30.4% progressing within 6 months of CAR T-cell infusion. The median time to progression following BsAb start was 48 days. Following POD, 70 pts received no further anti-lymphoma therapy. Among 98 pts receiving subsequent therapy, 85 initially received systemic therapy and 13 initially received local therapy with radiation (concurrently with systemic therapy in 8 pts). The most commonly-used next line of systemic therapies included: loncastuximab tesirine in 19 pts (ORR 16.7%, all PR); commercial CAR T in 11 pts (ORR 50% [CR 36.4%, PR 18.2%); tafasitamab with lenalidomide in 7 (no responses); and other chemotherapy in 46 pts (ORR 27.6% [CR 24.1%]). The median follow-up time from POD was 9.2 months among survivors (95% confidence interval [CI] 7.8-13.3). Among those who initiated subsequent-line therapy following BsAbs, the median progression-free survival (PFS2) was 1.9 months (95% CI 1.5-2.4) and median overall survival (OS) from initiation of subsequent-line therapy was 3.9 months (95% CI 2.4-5.5). The estimated 1-year OS following initiation of next therapy was 12%. Conclusions: We report the outcomes of largest cohort of pts with POD post-BsAbs in r/r LBCL. Progression events occurred early after initiation of single agent BsAbs, and almost half of pts who progressed did not receive subsequent therapy. For those who received standard subsequent-line therapy after POD, response rates and survival outcomes were poor. Pts with POD after BsAB should be strongly considered for clinical trials of novel therapeutics or combination therapies.

Abstract Introduction: Epcoritamab (epco) and glofitamab (glofit) are bispecific antibodies (BsAbs) approved for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs). Their use is associated with relatively high response rates, with some patients experiencing prolonged remission. It is unclear whether continuous treatment beyond 12 months for pts in remission is beneficial, as continued immunosuppression may result in additional toxicity. We sought to report the outcomes of pts with prolonged remission and survival following BsAb administration. Methods: We performed a multicenter retrospective study including 21 US centers evaluating pts with r/r LBCLs receiving commercially available epco or glofit between 2023 and 2025. Baseline characteristics and outcomes were extracted from medical records. Efficacy and survival outcomes were assessed by site investigators and included overall response rate (ORR), complete and partial response (CR, PR) rates. Pts who responded to BsAbs and had ≥365 days of follow-up from initiation of BsAb treatment were included in the analysis. Results: As of May 15, 2025, a total of 312 pts with r/r LBCLs were treated with BsAbs (epco n=193, glofit n=119) with a median age of 66 years (interquartile range [IQR] 59-73) at BsAb start. Most were male (64.5%), had advanced stage disease (77.4%) and had ECOG performance status of ≤1 (93.3%) at BsAb start. Of 207 pts who had initiated treatment with BsAb ≥12 months prior to data cutoff, we identified 31 pts (15.0%) who had a response to BsAbs (19 epco, 12 glofit) and were alive without progression at 12-months post-BsAb initiation and included them in this landmark analysis. Of the cohort of 19 pts treated with epco, 6 discontinued due to reasons other than disease progression including CAR-T cell therapy (n=2), secondary malignancy (n=2), allogeneic transplant (n=1), or other reasons (n=1). Thirteen of 19 pts received ≥12 months of epco treatment, and, with a median follow-up of 16 months from the start of BsAb, 12 of 13 pts continued receiving epco beyond 12 months with one pt discontinuing after 12 months (observed for an additional 41 days prior to censoring). Of the cohort of 12 pts treated with glofit, 8 pts were observed after completing all planned therapy and 4 patients underwent allogeneic transplant. Among all 31 BsAb-treated patients alive and in remission at 12 months, at the time of data cutoff, 5 pts (12.9%) had progressed (2 previously treated with epco and 3 with glofit). Three of the 4 pts who underwent allogeneic transplant after prior glofit treatment experienced disease relapse. A total of 24 pts (77.4%) were alive at the time of last follow-up, with the causes of death being disease progression (n=1), secondary malignancy (n=1), infection (n=1), and unknown cause (n=4). Conclusions: In this large cohort of r/r LBCL pts treated with BsAbs monotherapy in the standard of care setting, a relatively small proportion of pts (15%) achieve the 12 month PFS landmark. In the absence of robust evidence for what constitutes best practice, different strategies are employed, including continuation of BsAb, observation as well as consolidation with allogeneic transplant or CAR T-cell therapy. Additional follow-up will be reported to help guide clinical decision making regarding the optimal management strategy for this high risk pt population.

Abstract Epcoritamab and glofitamab are CD20-directed bispecific antibodies (BsAbs) approved in the United States for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between 1 January 2023 and 15 October 2024 were collected from 21 United States institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 2.0-3.8 months), and median overall survival (OS) was 7.8 months (95% CI, 6.2-11.0 months). The 6-month PFS was 36% (95% CI, 30-44) and the 6-month OS was 60% (95% CI, 54-67). Both trial ineligibility and undetectable CD20 pre-BsAbs portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after BsAbs with a median time to progression of 3.7 months. This analysis including patients with R/R DLBCL shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 were associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL, and underscore the importance of target antigen expression.

Abstract Introduction: Multiple myeloma (MM) is a B-cell-derived malignancy associated with immune dysregulation. Anti-CD38 monoclonal antibodies (mAbs) therapies have shown improved outcomes in patients with MM. Silbermann et al. showed that anti-CD38 mAb-containing therapies lead to profound hypogammaglobulinemia and reduction in Ig gene repertoire. The effect of modern therapies such as CAR-T and bispecific antibodies (BsAbs) on B-cell repertoire has not been well described. In this study, we sought to investigate the effect of these therapies on B-cell repertoire in patients with MM. Methods: This is a single-institution retrospective observational study evaluating MM patients treated with anti-BCMA CAR-T and BsAbs. Baseline characteristics, laboratory data, treatment history, were extracted from medical records. Total unique sequences (TUS) and total sequences of IgH, IgK, and IgL were identified and quantified using clonoSEQ. Patients were classified in two groups: CAR-T and BsAbs. The primary objectives were (1) characterize changes in TUS and total sequences within IgH, IgK, and IgL before and after treatment, and (2) examine how the sequences evolve over time following CAR-T. Results: 76 MM patients received CAR-T or BsAbs. Among those, 22 CAR-T and 5 BsAbs patients had pre- and post-treatment sequences available. Median age at initiation of treatment was 66 years in the CAR-T group (42-81 y) and 65 years in the BsAbs group (48-71 y). Based on mSMART v3 criteria, 72% of CAR-T and 60% of BsAbs recipients were classified as high-risk. Median number of prior lines of therapy was 5 (2-8) in the CAR-T group and 6 (5-13) in the BsAbs group.CAR-T recipients were classified into early (<40 days) and late (>40 days), based on when the post-CAR-T treatment clonoSEQ assay was performed. Changes in TUS and total sequences of IgH, IgK, and IgL were calculated, and the averages were assessed independently. The mean early and late change in total unique IgH sequences were (-75, 586 and 131, 038, p=0.052), unique IgK (-57, 797 and 52, 586, p=0.020), and unique IgL (-22, 354 and 25, 056, p=0.011). A subgroup of 8 patients with sequential MRD reports post-CAR-T therapy were identified, six patients showed improvement in B-cell sequence dynamics and two patients showed a decrease over time. For patients who received BsAbs, results indicated a similar pattern, with an early decrease in B-cell repertoires, characterized by reductions in sequence diversity and quantity. Conclusions: Our analysis of B-cell repertoires following CAR-T revealed changes before and after treatment. Patients receiving CAR-T therapy showed a decline in the number of TUS and total sequences of IgH, IgK, and IgL, likely due to the lymphodepletion regimen, followed by a gradual restoration reflecting immune recovery. Longer follow-up and a larger cohort will be necessary to assess the implications of these B-cell repertoire changes on patient outcomes. Citation Format: Feba Miriam Jacob, Rodolfo Garza-Morales, Joseph G Hentz, Alex Wonnaparhown, Julia E. Wiedmeier-Nutor, Mariano Arribas, Gabriela Alatorre, Sharene Best, Jayden Poulignot, Udit Yadav, Saurabh Chhabra, P. Leif Bergsagel, Rafael Fonseca, Talal Hilal. Dynamics of B-cell repertoires following CAR-T and bispecific antibody therapy in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4537.