Monotherapy Trials Research Articles

AFM13 in Combination with Allogeneic Natural Killer Cells (AB-101) in Relapsed or Refractory Hodgkin Lymphoma and CD30 + Peripheral T-Cell Lymphoma: A Phase 2 Study (LuminICE)

Background and Significance Limited treatment options are available for patients with relapsed or refractory (R/R) Hodgkin lymphoma (HL) and no standard-of-care therapy is established for R/R peripheral T-cell lymphoma (PTCL); novel therapies to improve outcomes in these patients are required. AFM13 is a tetravalent, bispecific innate cell engager that binds CD16A on natural killer (NK) cells and CD30 expressed (CD30 +) on HL and PTCL cells, enhancing NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). AFM13 monotherapy trials in patients with R/R HL and PTCL have shown promising clinical activity and a tolerable safety profile (Sasse et al. Blood 2020; Kim et al. Cancer Res 2023). Recently, a Phase 1/2 study of AFM13 in combination with cord blood (cb)-derived NK cells in patients with R/R CD30 + lymphomas treated at the recommended phase 2 dose (n=35) achieved an objective response rate (ORR) of 94% and a complete response (CR) rate of 71% (Nieto et al. Blood 2022, oral presentation). AB-101 is a non-genetically modified, allogeneic, cryopreserved, off-the-shelf, cb-derived NK cell product optimized for enhanced ADCC through selection for the KIR-B haplotype and the CD16 F158V polymorphism. AB-101 has demonstrated potent killing of tumor cell lines in vitro and in vivo and preliminary results of a Phase 1/2 trial of AB-101 alone and in combination with rituximab in patients with R/R B cell non-Hodgkin lymphoma demonstrated AB-101 is well tolerated (Khanal et al. J Clin Oncol 2023). Combining AFM13 with AB-101 has the potential to synergistically enhance and redirect antitumor immune responses to target HL and CD30 + PTCL cells. Study Design and Methods This Phase 2, open-label, multi-center, multi-cohort study (NCT05883449) aims to evaluate the efficacy and safety of AFM13 in combination with AB-101 in patients with R/R HL and certain R/R CD30 + PTCL subtypes. PTCL subtypes permitted are PTCL not-otherwise specified, angioimmunoblastic T-cell lymphoma, and ALK-positive and -negative anaplastic large cell lymphoma (ALCL). Patients aged ≥18 years are planned for enrolment and patients with R/R HL must have received at least two prior lines of therapy including prior combination chemotherapy, brentuximab vedotin (BV) and a checkpoint inhibitor. Patients with R/R PTCL must have confirmed CD30 expression of ≥1% by immunohistochemistry and have received at least one prior line of combination chemotherapy; patients with ALCL must have received or been intolerant to BV. Prior autologous or allogeneic hematopoietic stem cell transplant is permitted. Exclusion criteria include treatment with any anti-cancer agent ≤21 days prior to enrolment, continuing toxicity from a prior therapy, central nervous system involvement, or previous treatment with AFM13 or NK cells. The primary objective is to determine the ORR (complete and partial responses) by Independent Radiology Committee (IRC) based on PET-CT per Lugano classification. Secondary objectives include safety and immunogenicity, complete response rate, duration of response and progression free survival. Treatment will be given intravenously (IV) over 48-day cycles for up to 3 cycles. A run-in phase will assess two dose levels of AFM13 and AB-101 in 4 cohorts (Figure). A standard lymphodepletion regimen of fludarabine (30 mg/m 2/day) and cyclophosphamide (300 mg/m 2/day) will be administered IV from Day −5 to Day −3 at the start of each treatment cycle. Following this, AFM13 (200 mg or 300 mg once weekly) will be given, with AB-101 (dose level 1 or 2, see Figure) given 1 hour later per cycle. Patients will also receive 6 ×10 6 IU of IL-2 subcutaneously at least 1 hour after each AB-101 dose. Cohorts 1 and 2 will enrol in parallel; cohorts 3 and 4 will start only if cohorts 1 and 2 are cleared per protocol safety criteria. After cycle 1 has completed for each subject enrolled in all 4 cohorts, an analysis of the safety and clinical responses will be performed to determine the two dose levels to be evaluated in the main study. In addition, an exploratory cohort (cohort 5) will begin enrolment of patients with CD30 + PTCL. Disease and efficacy assessments will be conducted at screening and on Day 43 (± 3 days) of each cycle.

O16-4 A phase 2 trial of nivolumab monotherapy in rare cancer patients with mismatch repair deficiency or MSI-high: ROCK trial (NCCH1709) from MASTER KEY Project

O16-4 A phase 2 trial of nivolumab monotherapy in rare cancer patients with mismatch repair deficiency or MSI-high: ROCK trial (NCCH1709) from MASTER KEY Project

Randomized controlled trial of KW-6356 monotherapy in patients with early untreated Parkinson's disease

IntroductionKW-6356 is a novel selective adenosine A2A receptor antagonist/inverse agonist. We evaluated the efficacy and safety of KW-6356 as monotherapy in patients with early, untreated Parkinson's disease (PD). MethodsThis was a randomized, placebo-controlled, double-blind study conducted in Japan to investigate the efficacy and safety of once-daily KW-6356 (3 or 6 mg/day) orally administered as monotherapy for 12 weeks in patients with early PD (NCT02939391). The primary endpoint was the least squares means of change from baseline in the MDS-UPDRS Part III total score. ResultsOverall, 168 patients were randomized and treated (KW-6356 3 mg/day n = 55; 6 mg/day n = 58, placebo n = 55); Week 12 completion rates were >90% per group. LS mean [95% CI] changes from baseline to Week 12 in MDS-UPDRS Part III total scores were −5.37 [-7.25, −3.48] for 3 mg/day, −4.76 [-6.55, −2.96] for 6 mg/day and −3.14 [−4.97, −1.30] for placebo. Changes from baseline were larger for both KW-6356 groups than for the placebo group at all time points. Secondary endpoints supported the primary findings with larger changes in MDS-UPDRS Part II, Parts II + III, and Total scores in the KW-6356 groups than in the placebo group. Treatment was well-tolerated; the most common treatment-emergent adverse events with KW-6356 were constipation (n = 4 [7.3%] and n = 6 [10.3%] in the 3 and 6 mg/day groups, respectively) followed by nasopharyngitis (n = 4 [7.3%] and n = 5 [8.6%] in the 3 and 6 mg/day groups, respectively). ConclusionKW-6356 monotherapy is well tolerated and more effective than placebo in patients with early, untreated PD.

Matching-Adjusted Indirect Comparison of the Long-Term Efficacy Maintenance and Adverse Event Rates of Lebrikizumab versus Dupilumab in Moderate-to-Severe Atopic Dermatitis.

Lebrikizumab and dupilumab are monoclonal antibodies approved for treating moderate-to-severe atopic dermatitis (AD). Both have demonstrated efficacy and safety over the 16-week SOLOs and ADvocate trials. However, AD is a chronic and relapsing inflammatory disease, and the long-term maintenance of efficacy is critical for achieving disease control from the perspective of patients, physicians, and regulatory agencies. This study aims to compare the long-term efficacy and safety of lebrikizumab every 4weeks (Q4W) and dupilumab every week or every 2weeks (QW/Q2W) among adult patients who have achieved treatment efficacy following the induction period of 16weeks. Lebrikizumab's efficacy was assessed using individual patient data (IPD) from the ADvocate 1 and 2 monotherapy trials. Dupilumab's efficacy was evaluated using aggregate data from the adult-exclusive SOLO-CONTINUE trial. Due to the absence of a common comparator trial arm, we employed an unanchored matching-adjusted indirect comparison (MAIC), a robust methodology widely accepted by health technology assessment (HTA) agencies. This re-weights ADvocate IPD to align with SOLO-CONTINUE's prognostic factors and effect modifiers. We compared lebrikizumab's adjusted outcomes with dupilumab outcomes at week52, focusing on 75% improvement in the Eczema Area and Severity Index from baseline (EASI-75), Investigator's Global Assessment (IGA) score of 0 or 1, and overall adverse event (AE) rates. Sensitivity analyses were conducted to test various combinations of matching variables. Adults on lebrikizumab Q4W were more likely to maintain IGA 0/1 through the 36-week maintenance period (weeks16-52) compared with those on dupilumab QW/Q2W [risk ratio (RR) 1.334; 95% confidence interval (CI) 1.02-1.74; p = 0.035]. Both treatments demonstrated comparable efficacy in terms of EASI-75 maintenance (RR 0.937; 95% CI 0.78-1.13; p = 0.490) and similar AE rates (RR 1.052; 95% CI 0.90-1.23; p = 0.526). Sensitivity analyses substantiated these findings. Our findings suggest that lebrikizumab Q4W may provide equal or superior long-term maintenance of efficacy measured with EASI-75 and IGA 0/1 compared with dupilumab QW/Q2W, with the advantage of requiring less frequent doses.

Olaparib plus Abiraterone for Metastatic Castration-resistant Prostate Cancer: Pharmacokinetics Data from the PROpel Trial

PROpel (NCT03732820) was a positive phase 3 trial that demonstrated a clinically significant improvement in radiographic progression-free survival with olaparib plus abiraterone versus placebo plus abiraterone in first-line metastatic castration-resistant prostate cancer. For a subset of PROpel patients, steady-state concentrations of olaparib, abiraterone, and Δ4-abiraterone were measured in blood samples collected before and at several time points after dose administration. The pharmacokinetics (PK) for each drug and metabolite were evaluated to determine whether any clinically relevant drug-drug interactions between olaparib and abiraterone occurred. The results demonstrate that steady-state PK parameters for olaparib and abiraterone in PROpel were comparable with those in monotherapy trials. Abiraterone steady-state exposures were similar between treatment arms. Δ4-Abiraterone had slightly lower steady-state exposures when abiraterone was administered in combination with olaparib. These results are consistent with a previous phase 2 study, supporting the conclusion that no clinically relevant PK-based drug-drug interactions occurred when olaparib and abiraterone were given in combination at their full monotherapy doses. Patient summaryWhen drugs are administered in combination, a key consideration is whether there are any interactions between the drugs that may affect their activity. We analyzed blood concentrations of olaparib and abiraterone in a subset of patients with prostate cancer from the PROpel trial to determine if there were interactions between these two drugs. We found that there was no significant effect on the profile of either drug when they were given together at the same doses used when each drug is given individually.

Comprehensive Systematic Review of Biomarkers in Metastatic Renal Cell Carcinoma: Predictors, Prognostics, and Therapeutic Monitoring.

Challenges remain in determining the most effective treatment strategies and identifying patients who would benefit from adjuvant or neoadjuvant therapy in renal cell carcinoma. The objective of this review is to provide a comprehensive overview of biomarkers in metastatic renal cell carcinoma (mRCC) and their utility in prediction of treatment response, prognosis, and therapeutic monitoring in patients receiving systemic therapy for metastatic disease. A systematic literature search was conducted using the PubMed database for relevant studies published between January 2017 and December 2022. The search focused on biomarkers associated with mRCC and their relationship to immune checkpoint inhibitors, targeted therapy, and VEGF inhibitors in the adjuvant, neoadjuvant, and metastatic settings. The review identified various biomarkers with predictive, prognostic, and therapeutic monitoring potential in mRCC. The review also discussed the challenges associated with anti-angiogenic and immune-checkpoint monotherapy trials and highlighted the need for personalized therapy based on molecular signatures. This comprehensive review provides valuable insights into the landscape of biomarkers in mRCC and their potential applications in prediction of treatment response, prognosis, and therapeutic monitoring. The findings underscore the importance of incorporating biomarker assessment into clinical practice to guide treatment decisions and improve patient outcomes in mRCC.

1957P Results from a phase I/II trial of tinostamustine monotherapy in advanced solid tumours (NCT03345485): Safety and efficacy in a subset of patients (pts) with soft tissue sarcoma (STS)

1957P Results from a phase I/II trial of tinostamustine monotherapy in advanced solid tumours (NCT03345485): Safety and efficacy in a subset of patients (pts) with soft tissue sarcoma (STS)

Multi-trial, aggregated, individual participant data mega-analysis of short-term antidepressant versus mood stabilizer monotherapy of bipolar type II major depressive episode.

Few studies have systematically examined the safety and effectiveness of antidepressant versus mood stabilizer monotherapy of bipolar II depression. To date, there are no aggregated or mega-analyses of prospective trials of individual participant-level data (IPD) to inform future treatment guidelines on the relative safety and effectiveness of antidepressant or lithium monotherapy. Data from a series of four independent, similarly designed trials of antidepressant or lithium monotherapy (where longitudinal IPD were available) (n = 393) were aggregated into an IPD dataset (i.e., mega-analysis). Hierarchical log-linear growth models were used to analyze primary outcome of change over time in Hamilton Rating Scale for Depression (HRSD) scores; while secondary outcomes examined Clinical Global Impressions severity (CGI/S) and change (CGI/C) scores, and change over time in Young Mania Rating (YMR) scores. Relative to lithium monotherapy, antidepressant monotherapy demonstrated significantly greater symptom reduction on HRSD scores across time (b = -2.33, t = -6.68, p < 0.0001), significantly greater symptom reduction on the CGI/S across time (b = -0.414, t = -6.32, p < 0.001), and a significant improvement in CGI/C across time (b = -0.47, t = -7.43, p < 0.0001). No differences were observed in change over time for YMR scores between antidepressant and lithium monotherapy (b = 0.06, t = 0.49, p = 0.62). Findings from this IPD mega-analysis of bipolar II depression trials suggest a divergence from current evidence-based guidelines recommending combined mood stabilizer plus antidepressant therapy. The current mega-analysis suggests that antidepressant monotherapy may provide superior short-term effectiveness without clinically meaningful increase in treatment-emergent hypomanic symptoms compared to lithium monotherapy.

Abstract PO-082: Antigen presentation and inflammatory effects on immune surveillance: Window of opportunity metformin monotherapy trial for squamous cell carcinoma of the head and neck (HNSCC)

Abstract Introduction: The tumor microenvironment frequently displays dysregulated cellular metabolism, which contributes to aggressive behavior of the tumor. Though the mechanism of effect is unclear, clinical data suggest an association between metformin and improved outcomes in head and neck squamous cell carcinoma (HNSCC). The aim of this study is to investigate post-metformin treatment effects on the tumor microenvironment (TME) of HNSCC by using spatial RNA sequencing data from a metformin monotherapy window-of-opportunity clinical trial. Methods: This was a single-center prospective clinical trial of metformin in patients with HNSCC and a plan for definitive surgical resection. Primary lesions were biopsied prior to treatment and compared to matched post-treatment surgical specimens. Following biopsy-proven HNSCC diagnosis, metformin was initiated at 500 mg/day and increased to 1,000 mg twice daily by day 6. Spatial RNA sequencing of 18,000+ genes in CD45, CD163, and PanCK segments was conducted using Nanostring’s GeoMx digital spatial profiling (DSP). Sequencing data was analyzed by using unbiased gene set enrichment analysis (GSEA) and reported as a rank in gene list from 18,000+ total genes for post- vs pre-treatment analyses. Results: In all HPV positive, post-treatment samples in all three segments, GSEA demonstrated enrichment of antigen presenting cell types including NK cells, monocytes, and dendritic cells (q&amp;lt; 0.001). Inflammatory and metabolism signatures (IFN-y, IFN-a, oxidative phosphorylation) were enriched after metformin monotherapy in HPV+ samples within the PanCK positive segment (q&amp;lt; 0.001). Epithelial mesenchymal transition (EMT) was noted to be positively enriched while plasma cell signatures were negatively enriched within in HPV- post-treatment samples in the CD163 segment (q&amp;lt; 0.001). Within the CD45 positive segment, enriched expression of mRNAs for ribosomal-protein subsets were noted in T-cell gene sets and not in B-cell gene sets; in the CD45 segment, cytoplasmic ribosomal proteins is the second-most enriched gene set from C2 canonical pathways gene sets. Conclusion: Antigen presentation, inflammation, and ribosomal protein encoding genes were enriched with metformin monotherapy in the window of opportunity setting for HNSCC. Ribosomal proteins may also play a role in antigen presentation and immune surveillance in the post-treatment setting. Further research is required to describe the TME effects of metformin monotherapy and its effects on treatment response. Citation Format: Derek S. Mann, Sruti Tekumalla, Amiti Jain, Jacob Riordan, Alban Linnenbach, Diana Menezes, Ubaldo Martinez-Outschoorn, Joseph M. Curry. Antigen presentation and inflammatory effects on immune surveillance: Window of opportunity metformin monotherapy trial for squamous cell carcinoma of the head and neck (HNSCC) [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-082.

A novel clinically applicable biomarker for testing HRD status based on the mutational signatures: Results for the phase 2 trial of olaparib maintenance monotherapy in patients with primary high-grade ovarian carcinoma (2271)

A novel clinically applicable biomarker for testing HRD status based on the mutational signatures: Results for the phase 2 trial of olaparib maintenance monotherapy in patients with primary high-grade ovarian carcinoma (2271)

Immune Checkpoint Inhibitors Serve as the First-Line Treatment for Advanced Head and Neck Cancer.

Immune checkpoint inhibitor (ICI) therapy has demonstrated substantial benefits for certain patients. We try to evaluate the merits and demerits of each immunotherapy to aid clinical treatment. We conducted a comprehensive search of the PubMed, Embase, and Cochrane databases for randomized clinical trials published as of June 10, 2023. Our study included published clinical trials of ICI monotherapy or combination therapy, along with data on treatment-related adverse events (TRAE). Data regarding survival efficacy and adverse events of each randomized controlled trial (RCT) were collected. The Bayesian random effects model was utilized for the network meta-analysis (NMA). This study incorporated 19 RCTs, involving 5900 patients. Among 14 treatment regimens, Pembrolizumab combined with chemotherapy emerged as the most promising primary treatment for overall survival (OS) and objective response rate (ORR). Toripalimab combined with chemotherapy exhibited the highest likelihood of becoming the primary treatment for extending progression-free survival (PFS). Durvalumab showed the lowest probability of adverse events, suggesting a safer profile compared with other drugs. Camrelizumab combined with chemotherapy demonstrated a heightened risk of adverse events. Dual ICI Nivolumab/Ipilimumab surpassed Durvalumab/Tremelimumab in terms of ORR and adverse events. The standard of care (SOC) regimen did not exhibit strong performance across the four outcome indicators. Our analysis suggests that the integration of chemotherapy agents with ICIs enhances its efficacy as a first-line treatment for patients with advanced head and neck cancer (HNC). 1 Laryngoscope, 134:749-761, 2024.

Baricitinib provides rapid and sustained improvements in absolute EASI and SCORAD outcomes in adults with moderate-to-severe atopic dermatitis

BackgroundBaricitinib is an oral selective Janus kinase 1/2 inhibitor approved for moderate-to-severe atopic dermatitis (AD) in adults.ObjectivesTo evaluate absolute Eczema Area and Severity Index (EASI) and SCORing of Atopic Dermatitis (SCORAD) outcomes over 16 weeks and to link disease severity categories to quality of life (QoL) improvements.MethodsThis post-hoc analysis included patients enrolled in Phase3 monotherapy (BREEZE-AD1/AD2) and topical corticosteroid (TCS) combination therapy (BREEZE-AD7) trials and analyzed baricitinib 2 and 4 mg vs. placebo. Categorical outcomes were analyzed using Fisher’s exact test.ResultsSignificantly more baricitinib-treated patients reached EASI ≤ 7 and SCORAD < 25 as early as week 1 in monotherapy and week 2 in TCS combination therapy, compared to placebo. Significant response vs. placebo was sustained until week 16 for EASI ≤ 7 (AD1/2 [p-value vs. placebo]: 2 mg = 19.9%, 4 mg = 25.4% [p = 0.001] and AD7: 2 mg = 40.4% [p = 0.087], 4 mg = 48.6% [p = 0.003]) and SCORAD < 25 (AD1/2: 2 mg = 12.2%, 4 mg = 19.4% [p = 0.001] and AD7: 2 mg = 30.3% [p = 0.025], 4 mg = 34.2% [p = 0.004]) severity categories. These effects were accompanied by rapid improvements in QoL.ConclusionBaricitinib-treated patients rapidly achieved recommended absolute EASI and SCORAD treatment outcomes which were sustained until week 16. Improvements in QoL were greater than EASI severity categories reflected, indicating that physician-assessed scores do not necessarily correlate with patients’ impression of AD severity.

393 Comparative efficacy of targeted systemic therapies for moderate-to-severe atopic dermatitis without topical corticosteroids: an updated network meta-analysis

Abstract The landscape of targeted systemic treatments for moderate-to-severe atopic dermatitis (AD) continues to expand. With limited head-to-head randomized controlled trials conducted in AD, a network meta-analysis (NMA) helps inform treatment decisions by providing indirect comparisons across therapies. This study aims to update an NMA presented in Silverberg et al. (2022), assessing the comparative efficacy of targeted systemic treatments without concomitant topical corticosteroids in moderate-to-severe AD by including the latest Phase 3 monotherapy data for lebrikizumab. Data from the two most recently published Phase 3 monotherapy trials for lebrikizumab in moderate-to-severe AD [ADvocate1 (NCT04146363); ADvocate2 (NCT04178967)] were included in the analyses along with other eligible Phase 3 or 4 randomized placebo-controlled trials for abrocitinib, baricitinib, dupilumab, tralokinumab and upadacitinib identified through a systemic literature review in Silverberg et al. (2022). Prespecified efficacy outcomes included ≥90% and ≥75% improvement in Eczema Area and Severity Index (EASI 90, EASI 75) from baseline, ≥4-point improvement in Pruritus Numerical Rating Scale from baseline (ΔNRS ≥4) and Investigator Global Assessment (IGA) score of 0 or 1 (clear or almost clear) with a ≥2-point reduction from baseline (IGA 0/1), at the primary endpoint timepoint for each study (Week 12 for abrocitinib, Week 16 for all other therapies). Bayesian NMA was performed with fixed-effect, random-effect and baseline risk-adjusted models; fit statistics and diagnostics were assessed. The odds ratio (OR), number needed to treat (NNT), placebo-unadjusted absolute response rate (ARR) and Surface Under the Cumulative RAnking curve (SUCRA) scores were estimated. Statistical significance was assessed by OR 95% credible intervals excluding 1. The updated NMA analysed 13 unique placebo-controlled trials involving 7105 patients in 32 arms across six targeted therapies. Fit statistics and diagnostics supported fixed-effect models for all outcomes analysed. All targeted therapies had significantly greater response rates compared with placebo across all outcomes. For EASI 90, upadacitinib 30 mg had the most favorable response estimates (ARR = 58.3%, OR = 23.1, NNT = 1.9, SUCRA = 98.5%), followed by abrocitinib 200 mg (ARR = 45.2%, OR = 13.5, NNT = 2.5, SUCRA = 84.3%), upadacitinib 15 mg (ARR = 43.7%, OR = 12.8, NNT = 2.6, SUCRA = 82.0%), dupilumab 300 mg (ARR = 27.3%, OR = 6.2, NNT = 4.7, SUCRA = 52.8%), abrocitinib 100 mg (ARR = 26.8%, OR = 6.0, NNT = 4.8, SUCRA = 48.4%), baricitinib 4 mg (ARR = 25.0%, OR = 5.5, NNT = 5.2, SUCRA = 45.5%) and lebrikizumab 250 mg (ARR = 23.6%, OR = 5.1, NNT = 5.6, SUCRA = 40.0%). A similar rank order was observed for EASI 75 [upadacitinib 30 mg (ARR = 72.3%, OR = 19.1, NNT = 1.7, SUCRA = 98.5%), abrocitinib 200 mg (ARR = 64.6%, OR = 13.3, NNT = 1.9, SUCRA = 87.3%), upadacitinib 15 mg (ARR = 59.8%, OR = 10.9, NNT = 2.1, SUCRA = 80.2%), dupilumab 300 mg (ARR = 45.3%, OR = 6.0, NNT = 3.0, SUCRA = 55.4%), abrocitinib 100 mg (ARR = 44.9%, OR = 5.9, NNT = 3.1, SUCRA = 53.5%) and lebrikizumab 250 mg (ARR = 44.7%, OR = 5.9, NNT = 3.1, SUCRA = 53.9%)]. For ΔNRS ≥4, upadacitinib 30 mg also had the most favorable response (ARR = 56.1%, OR = 12.9, NNT = 2.1, SUCRA = 99.0%), followed by abrocitinib 200 mg (ARR = 45.4%, OR = 8.3, NNT = 2.8, SUCRA = 83.6%), upadacitinib 15 mg (ARR = 42.9%, OR = 7.6, NNT = 3.0, SUCRA = 79.2%), dupilumab 300 mg (ARR = 33.9%, OR = 5.2, NNT = 4.0, SUCRA = 54.2%), lebrikizumab 250 mg (ARR = 33.9%, OR = 5.1, NNT = 4.1, SUCRA = 54.1%) and abrocitinib 100 mg (ARR = 31.5%, OR = 4.6, NNT = 4.5, SUCRA = 46.1%). For IGA 0/1, upadacitinib 30 mg (ARR = 61.8%, OR = 19.4, NNT = 1.9, SUCRA = 99.9%) and upadacitinib 15 mg (ARR = 48.1%, OR = 11.1, NNT = 2.5, SUCRA = 86.9%) had the most favorable estimates, followed by abrocitinib 200 mg (ARR = 39.3%, OR = 7.7, NNT = 3.2, SUCRA = 75.5%), dupilumab 300 mg (ARR = 32.4%, OR = 5.7, NNT = 4.1, SUCRA = 62.1%) and lebrikizumab 250 mg (ARR = 28.0%, OR = 4.7, NNT = 5.0, SUCRA = 49.1%). Baricitinib 2 mg and tralokinumab 300 mg were generally ranked lower across outcomes. Among targeted treatments for moderate-to-severe AD used without concomitant topical corticosteroids for 12–16 weeks, upadacitinib 30 mg remains the most efficacious therapy in this NMA, generally followed by abrocitinib 200 mg, upadacitinib 15 mg, dupilumab 300 mg and lebrikizumab 250 mg or abrocitinib 100 mg.

Five-year follow-up of KEYNOTE-087: pembrolizumab monotherapy for relapsed/refractory classical Hodgkin lymphoma

AbstractPrevious analyses of the phase 2 KEYNOTE-087 (NCT02453594) trial of pembrolizumab monotherapy demonstrated effective antitumor activity with acceptable safety in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). However, long-term response durability and outcome of patients who receive a second course after treatment discontinuation after complete response (CR) remain of clinical interest. We present KEYNOTE-087 data after >5 years of median follow-up. Patients with R/R cHL and progressive disease (PD) after autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV; cohort 1), salvage chemotherapy and BV without ASCT (cohort 2), or ASCT without subsequent BV (cohort 3), received pembrolizumab for ≤2 years. Patients in CR who discontinued treatment and subsequently experienced PD were eligible for second-course pembrolizumab. Primary end points were the objective response rate (ORR) using blinded central review and safety. The median follow-up was 63.7 months. ORR was 71.4% (95% confidence interval [CI], 64.8-77.4; CR, 27.6%; partial response, 43.8%). Median duration of response (DOR) was 16.6 months; median progression-free survival was 13.7 months. A quarter of responders, including half of complete responders, maintained a response for ≥4 years. Median overall survival was not achieved. Among 20 patients receiving second-course pembrolizumab, ORR for 19 evaluable patients was 73.7% (95% CI, 48.8-90.8); median DOR was 15.2 months. Any-grade treatment-related adverse events occurred in 72.9% of patients and grade 3 or 4 adverse events occurred in 12.9% of patients; no treatment-related deaths occurred. Single-agent pembrolizumab can induce durable responses, particularly in patients achieving CR. Second-course pembrolizumab frequently reinduced sustained responses after relapse from initial CR.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Bruton tyrosine kinase inhibitors (BTKi) block B-cell receptor pathway signaling, leading to growth inhibition and cell death in malignant B-cells. First-generation BTKi, ibrutinib (ibr) revolutionized treatment; however, inhibition of off-target kinases such as EGFR, HER2, TEC, and CSK may be associated with toxicities, including diarrhea, rash, bleeding, and atrial fibrillation (Afib), that limit its use. Zanubrutinib (zanu), a potent and selective next-generation BTKi, maximizes BTK occupancy and minimizes off-target effects. Here, we characterized the overall safety/tolerability of zanu and compared it with ibr in patients (pts) with B-cell malignancies using the zanu clinical safety database. Methods: Safety data were pooled from 10 clinical trials of zanu monotherapy; 2 of the included studies (ASPEN; ALPINE) compared zanu head to head with ibr. Pts with CLL/SLL, MCL, MZL, WM, FL and other B-cell malignancies were included. Treatment-emergent adverse events (TEAEs) were summarized using MedDRA preferred terms; adverse events of special interest (AESI) were defined using pooled terms. Rates of TEAEs, exposure-adjusted incidence rates (EAIRs), and prevalence over time of AESI were assessed. Results: Pooled analyses included 1550 pts treated with zanu. Median zanu exposure was 28.6 months with 31.2% of pts having treatment exposure of ≥36 mo. Most common nonhematologic AEs were upper respiratory tract infection (29.0%), diarrhea (19.9%), contusion (19.4%), cough (17.2%), and rash (16.2%); grade ≥3 nonhematologic AEs occurring in ≥5% of pts included pneumonia (7.9%) and hypertension (7.4%). The most common serious AE was pneumonia (7.5%). Zanu discontinuation due to AE occurred in 12.3% of pts; AEs leading to dose reduction occurred in 9.6%. Disease progression was the most common cause of death (7.2%); deaths attributed to AEs occurred in 5.6% of pts, and most (3.2%) were due to infections including COVID-19-related AEs. The most common AESI in the pooled zanu population and in ibr-treated pts from ASPEN and ALPINE (N = 422) were infections and hemorrhage (Table). With the exception of neutropenia, EAIRs were numerically lower for zanu versus ibr, most notably hypertension (0.57 vs. 1.15 person/100 person-months), anemia (0.54 vs. 0.84 person/100 person-months), and atrial fibrillation or flutter (0.15 vs. 0.70 person/100 person-months). Prevalence of zanu AESI tended to remain constant or decrease with longer follow-up. Conclusions: As BTKi therapy requires continuous treatment, long-term tolerability and low treatment discontinuation rates are needed for successful outcomes. zanu was well tolerated, with generally mild-to-moderate AEs that tended not to lead to treatment discontinuation. Prevalence of AESI generally trended down over time without emergence of new safety signals, supporting zanu as a good option for long-term treatment. Encore Abstract - previously submitted to EHA 2023 The research was funded by: BeiGene Keywords: Aggressive B-cell non-Hodgkin lymphoma, Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract. J. R. Brown Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Octapharma, Oncternal, MingSight, TG Therapeutics Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, SecuraBio, Sun, TG Therapeutics B. Eichorst Consultant or advisory role: Janssen, AbbVie, Gilead, AstraZeneca, BeiGene, MSD, Lilly Honoraria: Roche, AbbVie, BeiGene, AstraZeneca, MSD Research funding: Janssen, Gilead, Roche, AbbVie, BeiGene, AstraZeneca Educational grants: BeiGene P. Ghia Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo Oncology, MSD, Roche Honoraria: AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo Oncology, MSD, Roche Research funding: AbbVie, AstraZeneca, BMS, Janssen W. Jurczak Consultant or advisory role: Abbvie, Astra Zeneca, BeiGene, Lilly, Roche, Takeda Research funding: Abbvie, Astra Zeneca, BeiGene, Janssen, Lilly, Roche, Takeda B. S. Kahl Consultant or advisory role: BeiGene, Pharmacyclics, AstraZeneca, Abbvie, Janssen Other remuneration: BeiGene N. Lamanna Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Janssen, Pharmacyclics Research funding: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Octapharma, Oncternal, MingSight, TG Therapeutics T. Robak Honoraria: AstraZeneca, BeiGene, Janssen, Abbvie, Octapharma, Regeneron, GSK Research funding: BeiGene,OctaPharma, AstraZeneca, Janssen, Regeneron, GSK, Educational grants: AstraZeneca M. Shadman Consultant or advisory role: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys/Incyte, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio, Regeneron, Merck, Fate therapeutics, MEI pharma and Atara Biotherapeutic Research funding: Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, AbbVie, TG Therapeutics, Beigene, AstraZeneca, Sunesis,Atara Biotherapeutics, Genmab, Morphosys/Incyte C. S. Tam Honoraria: BeiGene, AbbVie, Janssen Research funding: Janssen, AbbVie Other remuneration: BeiGene L. Qiu Consultant or advisory role: Janssen, Astra Zeneca, Takeda, Roche, Abbvie, Beigene A. Cohen Employment or leadership position: BeiGene Stock ownership: BeiGene M. Zhang Employment or leadership position: BeiGene T. Salmi Employment or leadership position: BeiGene International GmbH Stock ownership: BeiGene Ltd. J. Paik Employment or leadership position: BeiGene L. Wang Employment or leadership position: BeiGene Stock ownership: BeiGene J. Zhang Employment or leadership position: BeiGene Stock ownership: BeiGene H. Ma Employment or leadership position: BeiGene Stock ownership: BeiGene A. Tedeschi Consultant or advisory role: BeiGene, AstraZeneca, AbbVie, Janssen Honoraria: BeiGene, AstraZeneca, AbbVie, Janssen

Outpatient administration of mosunetuzumab in US community practice settings: perspectives and learnings from the Phase II MorningSun study

Outpatient administration of mosunetuzumab in US community practice settings: perspectives and learnings from the Phase II MorningSun study

Pembrolizumab immunotherapy in advanced and recurrent/metastatic salivary gland carcinoma (R/M SGC): A systematic review and meta-analysis.

e18101 Background: Treatment options for advanced R/M SGC are a limited and with variable response rates due to their safety/toxicity profile and the heterogenous l histology. Recent clinical trials tested pembrolizumab (PMB), a PD-1 inhibitor, in diverse settings. Methods: We performed a systematic review and single arm meta-analysis of clinical trials of PMB monotherapy or combined therapy in advanced and R/M SGC. PubMed, Scopus, and Cochrane database were searched for clinical trials published up to January 31, 2023. Data were extracted from published reports and quality assessment was performed per Cochrane recommendations. The primary endpoints of interest were complete/partial response (CR,PR) and disease control (DC= SD or better response) per RECIST v1.1, at any period of the trial. Results: Out of 199 database results, 4 clinical trials and 180 patients were included, all were using some form of PMB therapy. Overall, PMB was associated with a CR,PR ratio of 5.6% (95% CI 0.01-0.10, I²=25%, p=0.262) and DC ratio of 58.4% (95% CI 0.50-0.66, I²=13%, p=0.326), somewhat similar to recent evidence of PD-1/CTLA-4 combined therapy (nivolumab + ipilimumab [CR,PR=6-16%) in ongoing phase II clinical trials or PD-1 monotherapy (nivolumab [CR,PR=6%; SD=50%] in a completed clinical trial. Other systemic therapies, in which the current guidelines are based, include TKI (lenvatinib + sorafenib PR=3-15%; SD=50-94%) for adenoid cystic carcinoma (ACC); NTRK (larotrectinib CR,PR=90%, entrectinib CR,PR=86%), HER2 (transtuzumab associations CR,PR=60-90%), and AR (leuprorelin + bicalutamide CR,PR=42%, enzalutamide PR=4-15%; SD=52%) in non-ACC; and cytotoxic chemotherapy associations CR,PR=16-34% in heterogeneous histology tumors. Conclusions: There are marked limitations to the applicability of these findings in clinical practice, therefore a cautionary approach to this data is recommended, given their overall low statistical power, heterogenous histology, and tolerability to adverse effects. New trials with better standardized outcomes and comparative arms for different therapy associations and populations will help clarify the effects PD-1 inhibitors in the treatment of advanced and R/M SGC. [Table: see text]

Phase 1/2 study of tiragolumab and atezolizumab in patients with relapsed or refractory SMARCB1 or SMARCA4 deficient tumors.

TPS10066 Background: The SMARCB1/A4 gene products are core subunits of the SWItch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex. Tumors with defects in SWI/SNF are histologically distinct aggressive cancers occurring in children and young adults. SMARCB1/A4 deficient tumors, particularly rhabdoid tumors, poorly differentiated chordoma, epithelioid sarcoma, and medullary renal cell carcinoma, have immune cell infiltrates and programmed death ligand 1 (PD-L1) expression. Response to immune checkpoint inhibition (CI) has been observed in SMARCB1/A4 deficient tumors; however, responses are not durable. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel inhibitory receptor expressed on multiple immune cells. TIGIT inhibits T and NK cells by binding to its ligand poliovirus receptor (PVR) and Nectin2 on tumor cells and antigen-presenting cells. Utilizing RNAseq data, SMARCB1/A4 deficient tumors demonstrate high expression of PVR and Nectin2. Tiragolumab is an antibody to the TIGIT receptor. In patients with non-small cell lung cancer, tiragolumab with atezolizumab increased survival compared to atezolizumab alone. Thus, data suggest that SMARCB1/A4 deficient tumors are susceptible to CI; however, monotherapy is unlikely to achieve durable responses; the addition of tiragolumab may enhance response rates. Methods: This is a phase 1/2 trial of tiragolumab monotherapy and in combination with atezolizumab in patients ≥ 12 months of age with SMARCB1/A4 deficient tumors administered IV on Day 1 of 21-day cycles. Part A will evaluate the safety of tiragolumab monotherapy (300 mg if ≤ 15 kg; 420 mg if &gt;15 to ≤ 40 kg; 600 mg if &gt; 40 kg or ≥ 18 yrs) based on cycle 1 DLTs in up to 6 evaluable patients &lt;18 yrs of age. Part B will estimate the antitumor activity of tiragolumab in combination with atezolizumab (15 mg/kg [max 1200 mg]) if &lt; 18 yrs or 1200 mg if ≥ 18 yrs) in 6 histology-specific cohorts (renal medullary carcinoma, malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, poorly differentiated carcinoma, epithelioid sarcoma, and other) Each cohort will be conducted using a 6+4 Simon’s two stage design. Up to 13 patients may enroll in each cohort allowing for inevaluable patients (maximum n=78). Enrollment of patients ≥ 18 yrs on Part B may occur concurrently with enrollment of patients &lt; 18 yrs on Part A. If the pediatric dose of tiragolumab is deemed safe, patients &lt;18 yrs old may be enrolled on Part B. Cycle 1 toxicities of the combination therapy will be monitored in Part B using a Bayesian Optimal Interval Design in patients &lt; 12 yrs of age. The secondary objectives are to characterize pharmacokinetics/anti-drug antibody and estimating progression free survival, overall survival, and duration of response. Enrollment is open for all Pediatric Early Phase Clinical Trial Network sites. Clinical trial information: NCT05286801 .

Biomarker analysis of phase II pembrolizumab maintenance treatment after chemotherapy response in patients with HER2-negative inflammatory breast cancer and triple-negative breast cancer.

1105 Background: Accumulating toxicities make indefinite chemotherapy unfeasible for many patients with metastatic/recurrent HER2-negative inflammatory breast cancer (IBC) or triple-negative breast cancer (TNBC). We conducted a single-arm phase II trial of pembrolizumab monotherapy to determine the efficacy of maintenance immunotherapy in patients with metastatic HER2-negative aggressive breast cancer and to identify biomarkers correlated with disease control. Methods: The study enrolled patients who had a complete response, partial response, or stable disease after a minimum of 3 cycles of chemotherapy for metastatic TNBC/IBC regardless of PD-L1 expression between 2015 and 2022. Pembrolizumab was administered at 200 mg every 3 weeks until disease progression, intolerable toxicity, or 2 years of exposure to the drug. The primary endpoint was the 4-month disease control rate (DCR), and the secondary endpoint was progression-free survival (PFS). Correlative studies were performed to determine associations between clinical response, and immune profiling consisting of T-cell clonality, immunophenotyping, and dendritic cell (DC) function with blood collected at baseline and after 2 cycles of pembrolizumab treatment. Results: Of 43 treated patients, 11 had metastatic IBC and 32 had TNBC. The median number of prior lines of chemotherapy for metastatic disease was 1. During a median follow-up of 11.4 months, 33 patients had progressive disease and 25 were deceased. The 4-month DCR was 58.1% (95% CI: 43.4%-72.9%) and the median PFS was 4.8 months (95% CI: 3.0-7.1 months). The median PFS of the metastatic IBC group (2.2 months) and TNBC group (4.8 months) did not differ significantly ( p = .12). Thirty-one patients discontinued treatment due to progressive disease rather than toxicity. Observed toxicities were consistent with the known profile of pembrolizumab. Correlative blood studies showed availability of PD-1 on CD8 T cells decreased on therapy. T-cell exhaustion markers 2B4, CTLA4, and TIM3 decreased in patients who had therapeutic benefit, while LAG3 increased in patients without benefit. During therapy, ex vivo cytokine synthesis (IL-6/IL-12/TNFα) by DCs was superior in patients who benefited from therapy and increased from pretreatment samples. High T-cell clonality at baseline predicted response to immunotherapy (10.4 vs 3.6 months, p = .04). Additionally, patients exhibiting the greatest clinical benefit also had a significant increase in T-cell clonality over the course of therapy (20% vs 5.9% mean increase, p = .04). Conclusions: Increased T-cell clonality and DC activity, along with reductions in T-cell exhaustion, were associated with prolonged disease control following pembrolizumab maintenance therapy, achieving acceptable disease control with manageable toxicity. Clinical trial information: NCT02411656 .

A phase II trial of nivolumab for patients with platinum-refractory recurrent or metastatic salivary gland cancer.

6092 Background: Salivary gland cancer is rare and has various pathological subtypes. With this rarity and heterogeneity, the therapeutic contribution of chemotherapy, including immune checkpoint inhibitors, for recurrent or metastatic salivary gland cancer (RM-SGC) has not been elucidated. The purpose of this trial was to investigate the efficacy and safety of nivolumab for patients with platinum-refractory RM-SGC. Methods: This open-label, single-arm, multicenter phase II trial was conducted at 9 centers in Japan. Eligible patients had platinum-refractory recurrent or metastatic salivary gland cancer with measurable lesions by RECIST v1.1 and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, or 2. Nivolumab 240 mg/body was administered intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). We set the null hypothesis at 3% and the expected at 15% with a one-sided alfa of 0.1 and power of 80%. Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results: Twenty-four patients (16 males; median age, 65.5 years [range, 34-78 years]) were enrolled between March 2018 and January 2022. Pathological types were salivary duct carcinoma (n = 10), adenoid cystic carcinoma (n = 6), adenocarcinoma not otherwise specified (n = 5), mucoepidermoid carcinoma (n = 2), and acinic cell carcinoma (n = 1). In the majority of cases the primary site was a major salivary gland (n = 21), namely the parotid gland in 16 patients and submandibular gland in 5. The primary endpoint of ORR was 8.3% (2/24, 80% CI, 2.2-20.6%), with 2 partial responses (PR) in patients with salivary duct carcinoma (2/10, ORR: 20.0%). DCR was 29.2% (7/24, 2 in PR and 5 in stable disease), and all of the other 17 patients（70.8%）showed progressive disease (PD) on first disease evaluation at 12 weeks. With a median follow up for survivors of 32.0 months, median PFS and OS were 3.0 months (95% CI, 2.8-3.2 months) and 25.0 months (95% CI, 10.9-39.1 months), respectively. There was no new safety concern with nivolumab monotherapy. Conclusions: This phase II trial of nivolumab monotherapy for patients with platinum-refractory RM-SGC did not meet its primary endpoint of ORR. Although nivolumab monotherapy may be worth further development in salivary duct carcinoma, these results may raise concerns over nivolumab monotherapy for RM-SGC. Translational research to elucidate the immune microenvironment of each pathological type is under investigation. Clinical trial information: UMIN000029636 .