Citations

Abstract Anti-CD19 immunotherapy tafasitamab is used in combination with lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant. Open-label, phase 1b, First-MIND study assessed safety and preliminary efficacy of tafasitamab + R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) ± lenalidomide as first-line therapy in patients with DLBCL. From December 2019 to August 2020, 83 adults with untreated DLBCL (International Prognostic Index 2-5) were screened and 66 were randomly assigned (33 per arm) to R-CHOP-tafasitamab (arm T) or R-CHOP-tafasitamab-lenalidomide (arm T/L) for 6 cycles. Primary end point was safety; secondary end points included end-of-treatment (EoT) overall response rate (ORR) and complete response (CR) rate. All patients had ≥1 treatment-emergent adverse event, mostly grade 1 or 2. Grade ≥3 neutropenia and thrombocytopenia occurred, respectively, in 57.6% and 12.1% (arm T) and 84.8% and 36.4% (arm T/L) of patients. Nonhematologic toxicities occurred at similar rates among arms. R-CHOP mean relative dose intensity was ≥89% in both arms. EoT ORR was 75.8% (CR 72.7%) in arm T and 81.8% (CR 66.7%) in arm T/L; best ORR across visits was 90.0% and 93.9%. Eighteen-month duration of response and of CR rates were 72.7% and 74.5% (arm T) and 78.7% and 86.5% (arm T/L); 24-month progression-free and overall survival rates were 72.7% and 90.3% (arm T) and 76.8% and 93.8% (arm T/L). Manageable safety and promising signals of efficacy were observed in both arms. Potential benefit of adding tafasitamab + lenalidomide to R-CHOP is being investigated in phase 3 frontMIND (NCT04824092). This study is registered at www.clinicaltrials.gov as #NCT04134936.

Background Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the FLCN gene. Patients with BHD syndrome have an increased risk of fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma. There is debate regarding whether colonic polyps should be added to the criteria. Previous risk estimates have mostly been based on small clinical case series. Methods A comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants in FLCN . Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of FLCN pathogenic variants. Results Our final dataset contained 204 families that were informative for at least one manifestation of BHD (67 families informative for skin manifestations, 63 for lung, 88 for renal carcinoma and 29 for polyps). By age 70 years, male carriers of the FLCN variant have an estimated 19% (95% CI 12% to 31%) risk of renal tumours, 87% (95% CI 80% to 92%) of lung involvement and 87% (95% CI 78% to 93%) of skin lesions, while female carriers had an estimated 21% (95% CI 13% to 32%) risk of renal tumours, 82% (95% CI 73% to 88%) of lung involvement and 78% (95% CI 67% to 85%) of skin lesions. The cumulative risk of colonic polyps by age 70 years old was 21% (95% CI 8% to 45%) for male carriers and 32% (95% CI 16% to 53%) for female carriers. Conclusions These updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.

e19553 Background: The combination of tafa + LEN has accelerated approval in the United States (2020) and conditional approval in Canada and Europe (2021) for R/R DLBCL in ASCT-ineligible adult pts. A tolerable safety profile for R-CHOP + tafa ± LEN in pts with newly diagnosed DLBCL in the Phase Ib First-MIND study (NCT04134936) was previously reported, with numerically superior efficacy for R-CHOP + tafa + LEN (ASH 2021; #3556). We report PK, PD, and immunogenicity of R-CHOP + tafa ± LEN in this first line setting. Methods: Eligible pts ≥18 years with treatment-naïve DLBCL, IPI 2–5, and ECOG PS 0–2 were randomized 1:1 to either six 21-day (D) cycles (C) of R-CHOP (R-CHO, D1; P, D1–5) + tafa (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafa + LEN (25 mg orally, D1–10) (Arm B). Secondary endpoints included tafa serum conc and number and percentage of pts developing anti-tafa Abs. Exploratory endpoints included natural killer (NK) cell, T-cell, and B-cell count in peripheral blood. Results: Data cut-off: 13 March 2021 for safety analysis, incl. ≥1 month follow-up after EoT visit for all pts; 15 September 2021 for efficacy. Tafa serum conc reached steady state by C3 (geometric mean trough conc: Arm A, 186.40–216.55 µg/mL; Arm B, 171.77–201.54 µg/mL) and steadily declined after treatment completion. Anti-tafa Abs were detected in 1/65 (1.5%) pts. This pt showed pre-existing tafa Abs at baseline, which decreased during treatment. Median NK cell count decreased from baseline at C1D8 but was at baseline or higher levels by EoT visit (Arm A) and C1D15 (Arm B; Table). T-cell count decreased from baseline at C1D8 in both arms but was at baseline level or higher by C1D15 (Arm A) and EoT visit (Arm B). Median B-cell count decreased from baseline to 0 cells/μL (Arm A, C1D15; Arm B, C1D8); at 6-month follow-up after EoT visit, B-cell count had recovered to measurable levels in ̃50% of pts. Conclusions: Tafa serum conc reached and maintained a therapeutic dose level in this first-line regimen and declined in line with known tafa half-life (̃16 days) after treatment completion; tafa levels were comparable between the two treatment arms. No pt developed treatment-induced or treatment-boosted anti-tafa Abs. Median NK-cell, T-cell, and B-cell counts were comparable between treatment arms in all cycles. Clinical trial information: NCT04134936. [Table: see text]

TPS7590 Background: Up to 40% of patients relapse or are refractory (R/R) to R-CHOP, the current standard of care for diffuse large B-cell lymphoma (DLBCL), indicating an unmet need, particularly in patients with high-intermediate and high-risk disease (IPI 3–5). POLARIX (NCT03274492) evaluated a modified regimen substituting polatuzumab vedotin for vincristine (pola-R-CHP), demonstrating modest improvement in PFS with no OS benefit between treatment arms. The addition of lenalidomide (LEN) to R-CHOP improved both PFS and OS in the ECOG-ACRIN E1412 trial but not in the Phase III ROBUST study, in which a lower dose of LEN was used, despite a positive trend toward 2-year PFS in a subgroup analysis. The chemo-free immunotherapy tafasitamab + LEN has received accelerated approval in the United States (2020), and conditional marketing authorization in Europe and Canada (2021) in adult patients with R/R DLBCL ineligible for ASCT based on L-MIND (NCT02399085). The primary analysis of First-MIND (NCT04134936), a Phase Ib randomized safety study of R-CHOP + tafasitamab ± LEN in patients with previously untreated and newly diagnosed DLBCL, demonstrated that adding tafasitamab + LEN does not impair dosing and scheduling of R-CHOP, with toxicities similar to those expected with R-CHOP alone (ASH 2021; #3556). frontMIND (NCT04824092) will investigate the efficacy and safety of R-CHOP + tafasitamab + LEN vs R-CHOP alone in previously untreated patients with high-intermediate and high-risk DLBCL. Methods: frontMIND is a Phase III, multicenter, randomized, double-blind, placebo-controlled study. Approximately 880 patients are planned to be randomized at ̃350 centers in North and South America, Europe, and Asia-Pacific. Eligible patients aged 18‒80 years with previously untreated local biopsy-proven, CD20+ DLBCL with IPI score 3–5 (age-adjusted IPI 2–3 if ≤60 years), and ECOG PS 0–2 will be enrolled. Patients with transformed lymphoma (except double or triple hit lymphoma) are excluded. Patients will be randomized 1:1 to receive six 21-day (D) cycles of either R-CHOP + tafasitamab (12 mg/kg intravenously, D 1, 8, and 15) + LEN (25 mg orally, D1–10) or R-CHOP + tafasitamab and LEN placebos. Patients will be followed for up to 5 years after the end of treatment. The primary endpoint is investigator-assessed PFS. Secondary endpoints include investigator-assessed event-free survival, OS, safety, and tafasitamab serum concentration (trough and Cmax levels). Sensitivity and specificity of minimal residual disease for early detection of disease progression is an exploratory endpoint; further MRD parameters may also be investigated. The study is funded by MorphoSys AG and conducted with the scientific support of members of the Fondazione Italiana Linfomi and the German Lymphoma Alliance. Clinical trial information: NCT04824092.

9520 Background: Capmatinib (INC280) has shown promising efficacy in patients (pts) with MET exon 14 ( METex14)–mutated NSCLC who were pretreated (cohort 4) or treatment (tx)-naïve (cohort 5b) in the ongoing, multicohort, phase 2 GEOMETRY mono-1 study. We report the results for pts enrolled in the expansion cohort 6 with either high-level MET amplification (gene copy number [GCN] ≥10) or METex14 mutation (any MET GCN) whose disease progressed on 1 prior line of systemic therapy. Methods: Adult pts (≥18 years), ECOG PS 0–1 who had ALK and EGFR wt, stage IIIB/IV NSCLC (any histology) received capmatinib tablets 400 mg twice daily (with or without food). Key efficacy endpoints were overall response rate (ORR) and duration of response (DOR) by blinded independent review committee (BIRC) per RECIST v1.1. Other secondary endpoints included investigator-assessed ORR, DOR, disease control rate (DCR), progression-free survival (PFS; BIRC and investigator assessment) and safety. Results: As of Jan 6, 2020, 34 NSCLC pts with METex14 mutation (n = 31) or high-level MET amplification (n = 3) were included in this analysis. Tx was ongoing for 38.2% of pts. In METex14-mutated NSCLC pts, per BIRC assessment: ORR was 48.4%, median DOR was 6.93 months (mo, not yet mature, 95% CI: 4.17–NE) and median PFS was 8.11 mo (not yet mature, 95% CI: 4.17–9.86). Investigator-assessed responses were similar to BIRC assessment (Table). Only 3 pts with high-level MET amplification were included in this cohort due to challenges in enrollment. All 3 pts had stable disease per BIRC assessment and were on treatment for 48, 85 and 97 days. Most common AEs (≥25%, all grades, N = 34) were peripheral edema (64.7%), nausea (35.3%), fatigue (29.4%), back pain (26.5%) and vomiting (26.5%). Data for pts with brain metastasis will be presented at the ASCO 2020 meeting. Conclusions: Capmatinib was confirmed to be efficacious in 2nd line, METex14-mutated NSCLC pts. This is the first cohort where capmatinib has been administered without fasting restriction and data confirm the favorable safety profile. Clinical trial information: NCT02414139 . [Table: see text]