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Background & Aims: To evaluate safety and efficacy of FGFR1–3 kinase inhibitor derazantinib, in advanced intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions or rearrangements ( FGFR2 F ), mutations ( FGFR2 M ), or amplifications ( FGFR2 A ), previously treated with chemotherapy. Approach & Results: Open-label, non-controlled Phase 2 trial. Patients with advanced iCCA, ≥1 prior chemotherapy, and FGFR2 F (Substudy 1) or FGFR2 M /FGFR A (Substudy 2), received once-daily oral derazantinib 300 mg until disease progression, unacceptable toxicity, consent withdrawal or investigator decision to stop. Efficacy was assessed by central radiology review using RECIST v1.1. Primary endpoints were objective response rate (ORR; Substudy 1) and 3-month progression-free survival (PFS3; Substudy 2). Other endpoints were PFS, ORR (Substudy 2), disease control rate (DCR), duration of response (DOR), and overall survival (OS). In Substudy 1, ORR and DCR were 22.3% (23/103 partial responses) and 75.7%, respectively; median (95% CI) PFS was 8.1 (5.5,8.3) months, DOR was 6.5 (4.6,9.2) months, and OS was 17.2 (12.5,22.4) months. In Substudy 2, PFS3 was 63% (27/43), ORR was 9.3% (3 partial, 1 complete response), DCR was 69.8%, and OS was 11.9 (8.4,15.9) months. There were no Grade 4 or 5 drug-related events. FGFR inhibitor class-specific toxicities included drug-related hyperphosphataemia (38%, Grade 3: 3%) and dry eye (36%). Nail disorders (10%, any grade or causality), stomatitis (5%), retinal events (5%), and palmar-plantar erythrodysesthesia (1%) were infrequent. Conclusions: In previously chemotherapy treated, FGFR-inhibitor-naïve patients with iCCA harboring FGFR2 fusions, mutations, or amplifications, derazantinib showed clinically meaningful efficacy with durable objective responses, and a manageable safety profile.

ImportanceThe prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone.ObjectiveTo assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes.Data SourcesLiterature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023.Study SelectionTwo blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach.Main Outcomes and MeasuresOverall and disease-free survival, postoperative morbidity, and mortality.ResultsThe analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperative and/or perioperative chemotherapy plus surgery (HR, 0.78 [95% CrI, 0.64-0.91]; 3-year difference, 90 deaths per 1000 patients) showed longer overall survival than surgery alone. Comparing the 2 modalities yielded similar overall survival (HR, 1.04 [95% CrI], 0.83-1.28]; 3-year difference, 15 deaths per 1000 patients fewer for CRT). Similarly, disease-free survival was longer for both modalities compared with surgery alone. Postoperative morbidity was more frequent after CRT plus surgery (odds ratio [OR], 2.94 [95% CrI, 1.01-8.59]) than surgery alone. Postoperative mortality was not significantly more frequent after CRT plus surgery than surgery alone (OR, 2.50 [95% CrI, 0.66-10.56]) or after chemotherapy plus surgery than CRT plus surgery (OR, 0.44 [95% CrI, 0.08-2.00]).Conclusions and RelevanceIn this meta-analysis of patients with AEG, both preoperative CRT and preoperative and/or perioperative chemotherapy were associated with longer survival without relevant differences between the 2 modalities. Thus, either of the 2 treatments may be recommended to patients.

Abstract Disease progression after frontline therapy for Diffuse large B‐cell lymphoma (DLBCL) is a clinically significant event. Patients who experience early progression or have refractory disease have especially poor outcomes. Simple, clinically applicable prognostic tools are needed for selecting patients for consideration for novel therapies and prognostication in the relapsed/refractory (R/R) setting. Model building was performed in patients from the Surrogate endpoints in aggressive lymphoma (SEAL) consortium with disease progression after frontline immunochemotherapy. The primary endpoint was overall survival (OS) measured from date of progression. Validation was performed in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and Danish National Lymphoma Register (LYFO) cohorts. Model performance was assessed using time‐dependent concordance indices (c‐statistic) and calibration with metrics evaluated at 2 years from progression. Note, 1234 of 5112 patients treated with frontline immunochemotherapy in the SEAL consortium developed progressive disease. Time to progression on immunochemotherapy and age at progression were strongly associated with post‐progression OS (both p < 0.001). A prognostic model was developed incorporating spline fit for both variables. The model had good concordance in the discovery (0.67) and validation sets (LYFO c = 0.64, MER c = 0.68) with generally good calibration. Time to progression on frontline therapy is strongly associated with post‐progression OS in DLBCL. We developed and validated a simple to apply clinical prognostic tool in the R/R setting. The useful prediction of expected outcomes in R/R DLBCL and can inform treatment decisions such as considerations for CAR‐T therapy as well as trial designs. The model is available in smartphone‐based point of care applications.

Abstract Nivolumab, an anti–programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to further evaluate its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least 2 prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4 of 92 patients). Median progression-free survival (PFS) was 2.2 months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946.

Abstract Great heterogeneity in survival exists for patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL). Three scoring systems incorporating simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used: the International Prognostic Index (IPI), revised IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We evaluated 2124 DLBCL patients treated from 1998 to 2009 with frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; or variant) across 7 multicenter randomized clinical trials to determine which scoring system best discriminates overall survival (OS). Median age was 63 years, and 56% of patients were male. Five-year OS estimates ranged from 54% to 88%, from 61% to 93%, and from 49% to 92% using the IPI, R-IPI, and NCCN-IPI, respectively. The NCCN-IPI had the greatest absolute difference in OS estimates between the highest- and lowest-risk groups and best discriminated OS (concordance index = 0.632 vs 0.626 [IPI] vs 0.590 [R-IPI]). For each given IPI risk category, NCCN-IPI risk categories were significantly associated with OS (P ≤ .01); the reverse was not true, and the IPI did not provide additional significant prognostic information within all NCCN-IPI risk categories. Collectively, the NCCN-IPI outperformed the IPI and R-IPI. Patients with low-risk NCCN-IPI had favorable survival outcomes with little room for further improvement. In the rituximab era, none of the clinical risk scores identified a patient subgroup with long-term survival clearly &lt;50%. Integrating molecular features of the tumor and microenvironment into the NCCN-IPI or IPI might better characterize a high-risk group for which novel treatment approaches are most needed.

7544 Background: Great heterogeneity in survival exists for patients (pts) newly diagnosed with aggressive BCL. Three scoring systems based on simple clinical parameters (age, lactate dehydrogenase, number/sites of involvement, stage, performance status) are widely used: the international prognostic index (IPI), revised-IPI (R-IPI), and National Comprehensive Cancer Network IPI (NCCN-IPI). We studied BCL pts treated with R-CHOP to determine which scoring systems best identifies subgroups with poor outcomes that might benefit from new approaches. Methods: Individual pt data from 7 multicenter trials (1998-2009) of pts with BCL (86% DLBCL) treated front-line with R-CHOP (or variant) were analyzed to determine whether IPI, R-IPI, or NCCN-IPI best discriminated overall survival (OS). The concordance index (c-index) from a proportional hazards model, stratifying on trial and induction therapy, quantified predictive accuracy of each scoring system. Results: 2561 pts (median age 63 yrs, 56% male) were classified into IPI, R-IPI, and NCCN-IPI risk groups (Table). With a median follow-up of 5 yrs, NCCN-IPI had the greatest absolute difference in OS estimates between the highest and lowest risk groups at 1, 3, and 5 yrs, and best discriminated OS (c-index = 0.631, Table). Conclusions: In an independent and large cohort of pts, NCCN-IPI performs best in risk-stratifying pts with aggressive BCL, readily distinguishing pts at high and low risk for treatment failure using clinical parameters (5-yr OS between 48 and 92%). Improvement over the simpler IPI appears incremental, and IPI may remain a valuable alternative. Work integrating molecular features of the tumor into the (NCCN-) IPI is in progress to define high risk groups where targeted novel approaches are needed most. [Table: see text]

7520 Background: We report results of a phase 2, open-label study of durvalumab (durva) in combination with R-CHOP or R2-CHOP (R-CHOP + lenalidomide) in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL). Methods: Subjects (≥18 y; ECOG 0–2) with previously untreated, high/high-intermediate risk DLBCL (IPI ≥3/NCCN-IPI ≥4) were stratified to durva + R-CHOP (Arm A, GCB DLBCL) or R2-CHOP for 6–8 cycles (Arm B, ABC DLBCL) based on cell of origin identified by gene expression followed by durva consolidation up to month 12 from start of induction. After FDA placed clinical holds on trials including combination therapy with checkpoint inhibitors and immunomodulatory agents, the study was revised to include both ABC and GCB in Arm A (durva + R-CHOP). The primary endpoint was complete response rate (CRR) at end of induction; secondary endpoints were rate of subjects continuing to consolidation, safety, and response in biological. Results: A total of 46 subjects were treated (safety; A/B, n=43/3); median age, 62/66 y; male, 61%/67%; ECOG 2, 19%/33%; Ann Arbor stage IV, 79%/33%; bulky disease: 49%/67%; double/triple-hit lymphoma, 30%/33%. As of Aug 2, 2018, 30/3 (A/B) had completed induction therapy, and 19 subjects (A) were ongoing. CRR (95% confidence interval) at end of induction was (A) 54% (37%-71%) and (B) 67% (9%-99%); 68%/67% (A/B) continued to consolidation therapy and were progression free at month 12. Safety profile was as expected for the components of the combination regimen with no new safety signal identified. Frequent treatment-emergent adverse events (TEAEs; ≥25%; A+B) included fatigue (61%), neutropenia (52%), peripheral sensory neuropathy (50%), nausea (46%), diarrhea (28%); constipation, decreased appetite, insomnia, pyrexia (24% each); and alopecia, dizziness, dyspnea, headache, stomatitis (22% each). Grade 3/4 TEAEs occurred in 84%/100% of subjects (A/B), and 3 subjects (2/1) died with no death related to study treatment. Follow-up for efficacy and safety is ongoing. Conclusions: Durva + R-CHOP combination therapy is safe and demonstrates encouraging response rates in subjects with high-risk DLBCL including double-hit lymphoma. Clinical trial information: NCT03003520.