Sirdesai, Shreerang

Background: A subset of follicular lymphoma (FL) patients will experience a ‘high-risk defining event’ (HRDE) that portends poor survival due to early progression of disease or transformation to diffuse large B cell lymphoma (TFL). Progression of disease within 24 months (POD24) from front-line immunochemotherapy (ICT) identifies patients with a subsequent five-year OS of 50% compared to a reference group of 90% (Casulo et al. JCO 2015). Although a robust surrogate endpoint for OS in clinical trials (Casulo et al. Blood 2022), it remains to be established if the OS of patents is influenced by the nature of the HRDE. In this study, we examined whether characteristics and clinical trajectory of those with relapsed/progressive FL is the same as that of patients experiencing TFL. Methods: We conducted an international retrospective analysis of newly diagnosed FL patients requiring treatment across 14 academic centres between 2002 and 2021 in the era of rituximab and PET-CT staging. Patients were included with grade 1-3A FL requiring first-line (1L) treatment (ICT, rituximab monotherapy or radiotherapy). We excluded patients with untreated FL, de novo TFL and those with <24 months follow up provided they did not experience a HRDE. Baseline clinical, imaging and laboratory values, treatment details and outcomes were collected. We defined HRDE groups as persistent (relapse or progression) FL within 24 months of 1L treatment (FL24), early TFL (<24 months of 1L treatment) or late TFL (>24 months of 1L treatment). Patients not experiencing a HRDE formed the FL reference group. Landmark overall survival (OS) analysis was performed by Cox regression using risk status as a time-varying covariate for time of HRDE. For the FL reference group, landmark was defined at 24 months after 1L treatment. Results: 501 patients met the inclusion criteria and were categorised as: reference FL (n=378), FL24 (n=50), early TFL (n=28), late TFL (n=15). 24 patients who died within 24 months of 1L treatment without documentation of preceding HRDE and were omitted. Median follow up for patients alive beyond 24 months was 5.1 years. Median age at diagnosis was 60 years, 91% had ECOG performance status 0-1 and 38% were high-risk (>3) FLIPI. 1L chemotherapy regimens included: bendamustine (59%), CHOP (24%), CVP (8%), other (9%); a majority received rituximab (80%) vs obinutuzumab (20%). Maintenance therapy was used in 54% of pts. Expectedly, those experiencing HRDE had an inferior OS compared to the reference group (HR 5.23, p<0.001)(Figure 1). However, among HRDE group, median OS significantly differed: early TFL patients (3.0 yrs) and FL24 (12.6yrs)(HR 2.27, p=0.02) (Table 1). There was no difference in OS after HRDE between early TFL and late TFL ( p=0.81). Biopsy was performed in 84% of TFL cases with no difference in OS between biopsy-proven vs clinically suspected cases ( p=0.23). Multivariate OS analysis assessing HRDE and treatment demonstrated no significant interaction between HRDE group and 1L chemotherapy ( p=0.52), monoclonal antibody ( p=0.29) or maintenance therapy ( p=0.27). Several established prognostic features at baseline were enriched in patients who went on to experience HRDE including: ECOG >1 ( p<0.001), raised LDH ( p<0.001), advanced-stage disease (( p<0.011) and high risk FLIPI ( p=0.005). Baseline FDG-PET was available in 259 patients. Adverse PET metrics were enriched in only early TFL, and not FL24 or late TFL patients, including high SUV max( p=0.009), total metabolic tumor volume ( p=0.015) and total lesional glycolysis ( p=0.01). Conclusions: HRDEs after 1L treatment are associated with inferior OS in FL compared with standard-risk patients. Unlike POD24, this study demonstrates disparate clinical outcomes between patients experiencing early progression with persistent FL and those experiencing TFL. Adverse metabolic characteristics on baseline FDG-PET also suggest biological distinction between HRDE subsets. These findings have important implications for epidemiological studies, biomarker development and clinical trials aiming to improve outcomes in this underserved high-risk FL cohort.

Background: B-cell maturation antigen (BCMA) is widely expressed on normal plasma cells and malignant plasma cells in multiple myeloma (MM). MEDI2228 is an antibody-drug conjugate (ADC) that targets the extracellular domain of human BCMA with preferential binding to membrane-bound versus circulating soluble BCMA. The ADC is comprised of a fully human antibody to BCMA, site- specifically conjugated to a DNA cross-linking pyrrolobenzodiazepine (PBD) dimer via a protease-cleavable linker. After cell surface binding to BCMA, MEDI2228 is internalized and cleaved in the lysosomal compartment, releasing the active PBD, which cross-links DNA and leads to apoptotic cell death. We report the results from a phase 1, first-in-human, open-label, dose-escalation and expansion trial (NCT03489525) that evaluated the safety, pharmacokinetics (PK), and clinical activity of MEDI2228 in patients (pts) with relapsed/refractory MM (R/R MM). Methods: Eligible pts were ≥18 years old with confirmed R/R MM as defined by International Myeloma Working Group consensus criteria, had measurable disease, and had an Eastern Cooperative Oncology Group performance status ≤1. Pts had to have progressed after treatment with three classes of standard-of-care anti-myeloma drugs, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs). Dose escalation was based on an accelerated titration design, with an mTPI-2 algorithm. During dose escalation, MEDI2228 was administered in sequentially ascending dose levels (0.0125, 0.025, 0.05, 0.1, and 0.2 mg/kg) intravenously every 3 weeks (Q3W). Due to dose-limiting toxicities (DLTs), the dose was de-escalated from 0.2 mg/kg to an intermediate dose level of 0.14 mg/kg. The primary endpoint was safety and tolerability. Secondary endpoints included assessment of preliminary efficacy, PK, and immunogenicity. Results: As of May 15, 2020, 82 pts received MEDI2228 during dose escalation and expansion. All pts had received prior therapy with an IMiD, PI, and mAb: lenalidomide, 76 (94%); pomalidomide, 68 (84%); bortezomib, 77 (95%); carfilzomib, 64 (79%); and daratumumab, 71 (87%). Pts received between 2-11 lines of prior regimens. At 0.2 mg/kg, 2 pts experienced DLTs (grade 3/4 thrombocytopenia) without bleeding; no DLTs were reported for other dose levels. The maximum tolerated dose was 0.14 mg/kg Q3W. Treatment-related adverse events (TEAEs) occurring in ≥20% of pts in the 0.14 mg/kg cohort were photophobia (53.7%), thrombocytopenia (31.7%), rash (29.3%), increased gamma-glutamyltransferase (24.4%), dry eye (19.5%), and pleural effusion (19.5%). No reports of keratopathy or visual acuity loss were observed in the 0.14 mg/kg cohort. The TEAE profiles at lower-dose levels were similar but with lower incidences compared with the 0.14 mg/kg level. Efficacy was demonstrated at all dose levels (dose, objective response rate [ORR], [n]): 0.0125 mg/kg, 33.3% [1/3]; 0.025 mg/kg, 16.7% [1/6]; 0.05 mg/kg, 33.3% [3/9]; 0.10 mg/kg, 27.8% [5/18]; 0.14 mg/kg, 61.0% [25/41]; 0.2 mg/kg, 40.0%, [2/5]. In the 0.14 mg/kg cohort, ORR was 61.0% (95% confidence interval [CI]: 44.5%, 75.8%); there were 10 (24.4%) very good partial responses (VGPRs), 15 (36.6%) partial responses, and 3 (7.3%) minimal responses. Four of the VGPR pts were immunofixation negative. Most (90.2%) pts in the 0.14 mg/kg cohort had received prior daratumumab. Median duration of response (DOR) in the 0.14 mg/kg cohort was not reached. MEDI2228 exhibited linear PK at doses of ≥0.05 mg/kg Q3W that was minimally impacted by circulating levels of soluble BCMA at baseline. There was no difference in BCMA expression by IHC in the bone marrow of responders compared with nonresponders. Thirty-six pts in the 0.14 mg/kg cohort discontinued treatment due to adverse events (n=24), progressive disease (n=8), patient decision (n=2), investigator decision (n=1), or death (n=1). Conclusion: MEDI2228 is a BCMA-targeted ADC that demonstrated clinical efficacy at all dose levels explored. MEDI2228 0.14 mg/kg Q3W had a manageable safety profile and an ORR of 61% in a heavily pretreated population with myeloma that is R/R post PI, IMiD, and mAb therapies. Disclosures Kumar: Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Sanofi: Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy. Bhutani:Sanofi Genzyme: Consultancy; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Prothena: Other: Clinical Trial Funding to Institute; Janssen: Other: Clinical Trial Funding to Institute. Spencer:Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; Servier: Consultancy, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support; Pfizer: Consultancy, Honoraria; Takeda: Honoraria, Other, Speakers Bureau; Secura Bio: Consultancy, Honoraria; TheraMyc: Consultancy, Honoraria; Antegene: Consultancy, Honoraria; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; Pharmamar: Other. Ailawadhi:Cellectar: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Takeda: Honoraria; Amgen: Research Funding; Celgene: Honoraria; Phosplatin: Research Funding; Medimmune: Research Funding; BMS: Research Funding. Kalff:Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; CSL: Honoraria. Pore:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Gibson:AstraZeneca: Current Employment, Other: Paid as a clinical scientist contractor. Wang:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Cheng:Astrazeneca: Current Employment, Current equity holder in private company. Williams:AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Kinneer:AstraZeneca: Current Employment, Current equity holder in publicly-traded company, Other: Personal fees; BCMA Monoclonal Antibody-Drug Conjugate: Patents & Royalties: Pending. Zonder:Intellia: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Alnylam: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Oncopeptide: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; BMS: Consultancy, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Other: Personal fees; Prothena: Consultancy; Caelum: Consultancy; Celgene: Research Funding. Larsen:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; GSK: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Oncopeptide: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau.