Yimer, Habte

Abstract Introduction RCHOP is the standard frontline treatment for patients with DLBCL. However, for patients with high-intermediate or high-risk disease (IPI 3-5), outcomes are suboptimal, with an estimated 3-year PFS of about 55%. In addition to IPI, an additional factor associated with an increased risk include non-GCB cell of origin. Brentuximab vedotin, an ADC targeting CD30, has demonstrated single-agent activity in relapsed/refractory DLBCL patients. Of note, higher ORR and CR, as well as longer duration of PFS, were observed in those patients with CD30 detected on tumor cells by routine IHC. Methods This phase 2 study was designed to evaluate combination therapy using brentuximab vedotin (BV) and standard RCHOP chemotherapy as frontline treatment in patients with high-intermediate/high risk (standard IPI score 3-5 or age-adjusted IPI [aaIPI] score 2-3) DLBCL, regardless of CD30 expression (ClinicalTrials.gov NCT01925612). Patients were randomized to receive either 1.2 mg/kg BV+RCHOP or 1.8 mg/kg BV+RCHOP for up to 6 cycles of treatment. BV was given on Day 1 of every 21-day cycle. Response was assessed per investigator using Cheson 2007. AEs, physical examination findings, and laboratory testing were utilized to characterize safety. Tumor cell CD30 expression was measured by IHC and gene expression analysis; soluble CD30 was measured in plasma. Tumor microenvironment was also evaluated for frequency of immune-infiltrating cells. The primary endpoints for this study were the tolerability of each regimen and the CR rate at the end of treatment (EOT). Key secondary endpoints included progression-free survival (PFS). Additional exploratory endpoints included CD30 expression on tumor specimens (CD30- defined as <1% per IHC) and correlation of CD30 expression and response. Results Twenty-nine patients were treated with 1.2 mg/kg BV+RCHOP and 22 patients were treated with 1.8 mg/kg BV+RCHOP. Over half (63%) were high-intermediate risk (IPI 3, aaIPI 2) and 37% were high risk (IPI 4-5, aaIPI 3). Most had Stage IV disease (71%) and 27% had an ECOG score of 2. AEs in ≥50% of patients included peripheral sensory neuropathy (63%), fatigue (61%), nausea (55%), and diarrhea (53%). Grade 3 or higher events occurred in 76% of patients; the most frequent were neutropenia (33%) and febrile neutropenia (31%). The PET-negative CR rate was 69% overall; CD30+ patients had a CR rate of 76% (19/25) compared with 63% (12/19) in CD30- patients by IHC. Although PFS data are still immature (median follow up of 8 months), the estimated PFS rate at 12 months was 82% (95% CI: 58, 93) in CD30+ patients and 56% (95% CI: 32, 75) in CD30- patients. 60% (3/5) of patients with CD30- ABC-DLBCL progressed versus 27% (3/11) of CD30+ ABC-DLBCL patients. Four patients with EBV+ DLBCL were treated and all achieved CR; 3 EBV+ patients remain in remission after a median follow-up of 12 months. Within the microenvironment, a higher percentage of CD3+ T-cells was observed in patients with CR (23%; range, 4-80%) than in those with PR (14%; range, 10-15%) or PD (11%; range, 5-15%). Of the 32 patients who have not yet progressed, 50% had ≥20% CD3+ cells compared to 18% of patients with PD (2/11). Other factors, including soluble CD30 levels and infiltrating CD68+ cells, were not associated with clinical outcomes. Conclusions Interim results demonstrate that adding BV to RCHOP results in a high rate of CR in this population of IPI 3-5 DLBCL. Patients with CD30-expression in the tumor appear to have a higher CR rate and fewer early progression events than patients with CD30- DLBCL. Furthermore, subsets of patients who have a particularly poor prognosis (CD30+ ABC subtype and EBV+ DLBCL) appeared to have a favorable outcome with BV+RCHOP. Evaluation of the tumor microenvironment showed that higher frequencies of infiltrating CD3+ cells were observed in the CR group, suggesting possible immunologic correlates of response. However, CD30 expression appears to have greater prognostic significance in this study despite the relatively small sample size. These results are intriguing and merit further testing in a randomized trial. Disclosures Yasenchak: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. The drug is being evaluated in this study for use as frontline treatment in patients with high-intermediate/high risk DLBCL in combination with multiagent chemotherapy. . Halwani:Abbvie: Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Takeda/Millenium: Research Funding; BMS: Research Funding; Seattle Genetics, Inc.: Other: Travel expenses, Research Funding; Roche/Genentech: Research Funding; Kyowa Hakko Kirin: Research Funding; Amgen: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding; Genetech: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Budde:Merck: Research Funding; Ikara Inc: Patents & Royalties; Atara Biotherapeutics: Consultancy; Seattle Genetics, Inc.: Research Funding. Burke:Millenium/Takeda: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel expenses; Gilead: Consultancy; Janssen: Consultancy; Seattle Genetics, Inc.: Research Funding. Farber:Seattle Genetics, Inc.: Research Funding. Holkova:Seattle Genetics, Inc.: Research Funding. Kolibaba:GSK: Research Funding; Seattle Genetics, Inc.: Research Funding; Acerta: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; TG Therapeutics: Research Funding. Knapp:Celgene: Research Funding; Heron Pharmaceuticals: Other: Travel expenses, Research Funding; Merck: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Brystol-Myers Squibb: Research Funding; Genentech: Honoraria, Other: Travel expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; EMD Serono: Research Funding. Li:Seattle Genetics, Inc.: Employment, Equity Ownership. Manley:Seattle Genetics, Inc.: Employment, Equity Ownership. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Seetharam:Seattle Genetics, Inc.: Research Funding. Yimer:Seattle Genetics, Inc.: Research Funding. Bartlett:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding.

Abstract Background: Patients on systemic therapy for cancer are at varying risk for venous thromboembolism (VTE) and its consequences. Thromboprophylaxis is recommended in hospitalized medical and surgical cancer patients, but most VTE occurs in ambulatory cancer patients where risk can be estimated with a validated score. However, the benefit of extended outpatient thromboprophylaxis is uncertain with heparins and has not been tested with direct oral anticoagulants. Methods: We conducted a double-blind, randomized, placebo-controlled, parallel-group, multicenter study in adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for VTE (defined as Khorana score ≥ 2). Enrolled subjects were screened for deep-vein thrombosis (DVT) and if none found randomized 1:1 to rivaroxaban 10 mg once daily or placebo up to day 180. Subjects were screened with lower extremity ultrasounds every 8 weeks on study. Primary efficacy endpoint was a composite of objectively confirmed symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper- or lower-extremity distal DVT, symptomatic or incidental pulmonary embolism and VTE-related death. ISTH-defined major bleeding was the primary safety endpoint. All endpoints were adjudicated by blinded independent committees. Analyses for efficacy endpoints were conducted for intent-to-treat (ITT) population (all randomized patients) for the up-to-day 180 observation period (primary) and the on-treatment period (supportive). Safety analyses were conducted for on-treatment period only for patients who received at least one dose of study drug. Results: Of 1,080 patients who provided consent, 49 (4.53%) had DVT on baseline screening and another 190 screen-failed due to other reasons. Of 841 randomized patients, 274 (32.6%) had pancreatic cancer; 698 (83%) were white and 428 (50.9%) were male. The primary efficacy endpoint occurred in 25 of 420 patients (5.95%) and 37 of 421 patients (8.79%) (HR, 0.66; 95% CI, 0.40 to 1.09; p=0.101) in the rivaroxaban and placebo groups respectively (number needed to treat, NNT=35) in the up-to-day 180 observation period (Figure 1A). Of all patients with VTE, 38.70% experienced events after discontinuing study drug. In a pre-specified analysis of all randomized patients during the on-treatment period, the primary endpoint occurred in 11 of 420 patients (2.62%) and 27 of 421 (6.41%) in rivaroxaban and placebo groups respectively (HR 0.40, 95% CI 0.20 to 0.80, p=0.007) (NNT=26) (Figure 1B). Major bleeding occurred in 8 of 405 (1.98%) in the rivaroxaban group and in 4 of 404 (0.99%) patients in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49; p=0.265) (number needed to harm, NNH=101). Clinically relevant non-major bleeding occurred in 2.72% and 1.98% of rivaroxaban and placebo groups, respectively (HR, 1.34; 95% CI, 0.54 to 3.32; p=0.53) (NNH=135). Adverse events were comparable between groups. For secondary efficacy endpoints, a pre-specified analysis of the composite of primary endpoint with addition of arterial and visceral thromboembolic events in the up-to-day 180 observation period showed significantly fewer events in rivaroxaban versus placebo group (6.90% versus 10.70% respectively; HR, 0.62; 95% CI: 0.39, 0.99; p=0.04). All-cause mortality occurred in 20.0% of patients in rivaroxaban group and 23.8% in placebo group (HR=0.83, 95% CI 0.62, 1.11; p=0.213). A pre-specified composite of the primary endpoint with all-cause mortality occurred in 23.1% of patients in rivaroxaban group and 29.5% in placebo group (HR 0.75; 95% CI 0.57 to 0.97; p=0.03) (Figure 1C). Conclusions: Rivaroxaban significantly reduced VTE and VTE-related death during the on-treatment period but not during the full study period; over one-third of events occurred post discontinuation of study drug. The incidence of major bleeding was low. The Khorana risk score cut-off of ≥2 identified cancer patients at high risk of thrombotic events both at baseline (4.53%) and during study (8.79% with additional 1.66% arterial events in placebo group). These results should inform future recommendations regarding thromboprophylaxis in at-risk ambulatory cancer patients. (Funded by Janssen; ClinicalTrials.gov number, NCT02555878) Figure 1 Figure 1. Disclosures Khorana: Parexel: Other: Personal fees and non-financial support for travel; Sanofi: Consultancy, Other: Personal fees and non-financial support for travel; Pfizer: Consultancy, Other: Personal fees and non-financial support for travel; Janssen: Consultancy, Other: Personal fees, Research Funding; TriSalus: Other: Personal fees; Halozyme: Other: Personal fees and non-financial support for travel; Seattle Genetics: Other: Personal fees and non-financial support for travel; AngioDynamics: Other: Personal fees and non-financial support for travel; LEO Pharma: Other: Personal fees and non-financial support for travel; Medscape/WebMD: Other: Personal fees and non-financial support for travel; Pharmacyclics: Other: Personal fees; PharmaCyte: Other: Personal fees; Bayer: Consultancy, Other: Personal fees and non-financial support for travel. Soff:Janssen: Research Funding; Amgen: Research Funding. Kakkar:Bayer AG: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Daiichi Sankyo Europe: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Sanofi S.A.: Consultancy; Verseon: Consultancy. Vadhan-Raj:AMAG Pharmaceuticals, Inc: Other: received funding from Amag to support clinical trial; Janssen: Consultancy, Research Funding. Riess:Janssen Scientific Affairs: Other: Travel reimbursement; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Wun:Eli Lilly, Inc.: Research Funding; Emmaus, Inc.: Membership on an entity's Board of Directors or advisory committees; Glycomimetics, Inc.: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees. Streiff:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Other: outcome adjudication committee; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Roche: Research Funding; Portola: Consultancy, Research Funding. Garcia:Shingoi: Consultancy; Portola: Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Research Funding; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Bristol Meyers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; Retham Technologies LLC: Consultancy; Genzyme Corporation: Consultancy; Alexion: Consultancy. Liebman:Janssen (Johnson & Johnson): Other: steering committee of the CASSINI trial during the conduct of the study. Belani:Janssen: Consultancy. O'Reilly:3DMed, Agios, AlignMed, Amgen, Antengene, Aptus, ASLAN, Astellas, AstraZeneca, Bayer, BeiGene, Bioline, BMS, Boston Scientific, Bridgebio, CARsgen, Celgene, CASI, Cipla, CytomX, Daiichi, Debio, Delcath, Eisai, Exelixis, Genoscience, Gilead, Halozyme: Consultancy; Hengrui, Incyte, Inovio, Ipsen, Jazz, Janssen, Kyowa Kirin, LAM, Lilly, Loxo, Merck, Mina, NewLink Genetics, Novella, Onxeo, PCI Biotech, Pfizer, PharmaCyte, Pharmacyclics, Pieris, QED, RedHill, Sanofi, Servier, Silenseed, Sillajen, Sobi, Targovax: Consultancy; Janssen: Research Funding; Acta Biologica, Agios, Array, AstraZeneca, Bayer, BeiGene, BMS, CASI, Celgene, Exelixis, Genentech, Halozyme, Incyte, Lilly, MabVax, Novartis, OncoQuest, Polaris Puma, QED, and Roche: Research Funding; Tekmira, twoXAR, Vicus, Yakult, and Yiviva: Consultancy. Patel:Janssen Pharmaceuticals: Research Funding. Yimer:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Epizyme: Equity Ownership; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership. Wildgoose:Janssen Scientific Affairs: Employment; Johnson & Johnson: Equity Ownership. Burton:Janssen Pharmaceuticals: Employment; Johnson & Johnson: Equity Ownership. Vijapurkar:Janssen Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Kaul:Janssen Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Eikelboom:AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, GlaxoSmithKline, Janssen, sanofi-aventis, and Eli Lilly: Honoraria, Research Funding; Heart and Stroke Foundation: Other: Personnel award. Bauer:Janssen: Consultancy. Kuderer:Celldex: Consultancy; Mylan: Consultancy, Other: Travel, Accommodations, Expenses; Myriad Genetics: Consultancy; Halozyme: Consultancy; Coherus Biosciences: Consultancy, Other: Travel, Accommodations, Expenses; Janssen Scientific Affairs, LLC: Consultancy, Other: Travel, Accommodations, Expenses; Pfizer: Consultancy; Bayer: Consultancy. Lyman:Halozyme; G1 Therapeutics; Coherus Biosciences: Consultancy; Generex Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Research support.