Christian, Beth

Abstract Introduction This phase 1/2 study evaluated the safety and antitumor activity of brentuximab vedotin (BV) administered in combination with nivolumab (Nivo) in adult patients (pts) with relapsed/refractory classic Hodgkin lymphoma (R/R cHL) who have failed frontline therapy (NCT02572167). Results from Parts 1 & 2 have been previously reported, wherein safety, efficacy, and biomarkers consistent with immune activation were observed in pts with R/R cHL (Herrera et al., Blood 2018). In Part 3, patients were treated with BV + Nivo on Day 1 of each cycle. In contrast, pts in Parts 1 & 2 received BV on C1D1 and Nivo on C1D8 with concurrent admin on subsequent cycles. Herein we present safety, efficacy, and biomarker results for Part 3 and updated progression free survival (PFS) from Parts 1 & 2. Methods Pts in Parts 1 & 2 received up to four 21-day cycles of staggered dosing (day 1 BV 1.8 mg/kg, day 8 Nivo 3 mg/kg in Cycle 1) and concurrent thereafter, with steroid and antihistamine premedication. Pts in Part 3 received up to four 21-day cycles of concurrent BV + Nivo on Day 1 with antihistamine premedication. Following Cycle 4 response assessment (Lugano Classification Revised Staging System with the incorporation of the Lymphoma Response to Immunomodulatory Therapy Criteria [LYRIC, 2016]) responding pts were eligible to undergo autologous stem cell transplant (ASCT). Results 30 pts were treated in Part 3 and all were evaluable for efficacy. Pt characteristics included the following: median age 31.5 yrs (range; 20 - 66), 63% female, 93% prior ABVD, 37% primary refractory HL, 30% relapsed within 1year of frontline therapy, 30% with extranodal disease and 17% with bulky disease at enrollment. 28 pts completed all 4 cycles. 1 pt discontinued treatment (tx) due to an adverse event (AE; Grade 3 [G3] elevated Gamma-Glutamyltransferase) and 1 pt due to progressive disease (PD). The latter pt eventually died due to PD. All pts are off tx and have been observed through the safety reporting period. 37% of pts experienced a G3 or higher tx emergent AE prior to ASCT. 30% of the pts experienced infusion related reactions (IRRs), which occurred most frequently during Cycle 2. Potential G3 or higher immune-related AEs (IRAEs), excluding IRRs, occurred in 2 pts, one of whom required steroids for G4 pneumonitis, which subsequently resolved. Among the 30 efficacy evaluable pts, the complete response (CR) rate was 80% (24/30), with an objective response rate (ORR) of 93%. 47% of pts (14) had a Deauville ≤2, and 17% (5) had Deauville 3. 5 pts with CR had a Deauville >3 and met LYRIC criteria for IR-2. 4/5 pts had a negative follow-up biopsy that confirmed CR and in 1 pt the PET finding was considered to be a false positive as contrast enhanced CT did not reveal any abnormality. All 5 pts proceeded directly to ASCT and remain in CR at follow-up. Among all treated patients, 25 went directly to ASCT after completing BV + Nivo tx with a median 6.8 x 106 CD34+ cells/kg (range 1-20) collected. Median times to neutrophil and platelet engraftment were 12 and 14 days, respectively. 4 pts required additional salvage therapy subsequent to study tx. Patients were followed for a median of 6 months from ASCT (N=25, range 0.8-8.8) and 10 months from first dose (N=30, range 1.8-12.7). The estimated 9-month PFS rate in all-treated pts was 88%. This is comparable to all-treated pts in Parts 1 & 2, whose estimated 9 and 15 month PFS were 86% and 82%, respectively (Fig 2). Biomarker testing was performed on peripheral blood samples, included immunophenotyping, serum cytokine analysis, and TCRβ sequencing. Concurrent dosing of BV+ Nivo resulted in increased levels of both activated and dividing CD4+ and CD8+ T cells, as well as increased regulatory T-cells and circulating plasmablasts. Cytokines and chemokines associated with innate and adaptive immune activation, including Type I and Type II interferons, IL-18, and IP-10, were significantly upregulated following BV + Nivo, while TARC levels were significantly diminished following therapy. TCRβ sequencing revealed clonal expansion in the periphery following BV + Nivo. Conclusion A concurrent dosing schedule of BV + Nivo was well tolerated with a high CR rate of 80%. Biomarkers evaluated in Part 3 indicate immune activation in the periphery following BV + Nivo. Cumulatively, the results in Part 3, along with the durable remissions noted in Parts 1 & 2, support BV + Nivo combination as an encouraging first salvage therapy prior to ASCT in pts with R/R cHL. Disclosures Advani: Forty Seven: Research Funding; Infinity: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Merck: Research Funding; Agensys: Research Funding; Millenium: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding. Moskowitz:Bristol Myers-Squibb: Consultancy, Research Funding; Incyte: Research Funding; Takeda: Honoraria; Merck: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Bartlett:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vose:Celgene: Research Funding; Legend Pharmaceuticals: Honoraria; Bristol Myers Squibb: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Incyte Corp.: Research Funding; Roche: Honoraria; Novartis: Honoraria, Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta Pharma: Research Funding; Abbvie: Honoraria; Epizyme: Honoraria; Kite Pharma: Research Funding. Ramchandren:Merck: Research Funding; Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Feldman:Johnson and Johnson: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Portola: Research Funding; Janssen: Speakers Bureau; KITE: Speakers Bureau. LaCasce:Seattle Genetics: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Humanigen: Consultancy, Honoraria. Christian:Acerta: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Immunomedics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:LAM Therapeutics: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Takeda: Research Funding. Moskowitz:Celgene: Consultancy; Merck & Co: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Ogden:Seattle Genetics, Inc: Employment, Equity Ownership. Taft:Seattle Genetics: Employment, Equity Ownership. Zak:Seattle Genetics: Employment, Equity Ownership. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Galderisi:Seattle Genetics: Employment, Equity Ownership. Herrera:Immune Design: Research Funding; Merck, Inc.: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences: Research Funding.

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin’s lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.

BackgroundThis multicenter, randomized phase 2 trial evaluated complete responses (CRs), efficacy, and safety with ofatumumab and bendamustine and with ofatumumab, bendamustine, and bortezomib in patients with untreated, high‐risk follicular lymphoma (FL).MethodsPatients with grade 1 to 3a FL and either a Follicular Lymphoma International Prognostic Index (FLIPI) score of 2 with 1 lymph node >6 cm or an FLIPI score of 3 to 5 were randomized to arm A (ofatumumab, bendamustine, and maintenance ofatumumab) or to arm B (ofatumumab, bendamustine, bortezomib, and maintenance ofatumumab and bortezomib).ResultsOne hundred twenty‐eight patients (66 in arm A and 62 in arm B) received treatment. The median age was 61 years, and 61% had disease >6 cm; 29% had an FLIPI score of 2, and 71% had an FLIPI score of 3 to 5. In arm A, 86% completed induction, and 64% completed maintenance. In arm B, 66% and 52% completed induction and maintenance, respectively. Dose modifications were required in 65% and 89% in arms A and B, respectively. Clinically significant grade 3 to 4 toxicities included neutropenia (A, 36%; B, 31%), nausea/vomiting (A, 0%; B, 8%), diarrhea (A, 5%; B, 11%), and sensory neuropathy (A, 0%; B, 5%). The estimated CR rates were 62% (95% confidence interval [CI], 50%‐74%) and 60% (95% CI, 47%‐72%) in arms A and B, respectively (P = .68). With a median follow‐up of 3.3 years, the estimated 2‐year progression‐free survival (PFS) and overall survival (OS) rates were 80% and 97%, respectively, for arm A and 76% and 91%, respectively, for arm B.ConclusionsThe CR rates, PFS, and OS were not improved with the addition of bortezomib to ofatumumab and bendamustine in patients with high‐risk FL. Although grade 3 to 4 toxicities were similar, more patients treated with bortezomib required dose modifications and early discontinuation.