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Purpose: Because effective drug delivery is often limited by inadequate vasculature within the tumor, the ability to modulate the tumor microenvironment is one strategy that may achieve better drug distribution. We have previously shown that treatment of mice bearing tumors with phosphoinositide-3 kinase (PI3K) inhibitors alters vascular structure in a manner analogous to vascular normalization and results in increased perfusion of the tumor. On the basis of that result, we asked whether inhibition of PI3K would improve chemotherapy delivery.Experimental Design: Mice with xenografts using the cell line SQ20B bearing a hypoxia marker or MMTV-neu transgenic mice with spontaneous breast tumors were treated with the class I PI3K inhibitor GDC-0941. The tumor vasculature was evaluated by Doppler ultrasound, and histology. The delivery of doxorubicin was assessed using whole animal fluorescence, distribution on histologic sections, high-performance liquid chromatography on tumor lysates, and tumor growth delay.Results: Treatment with GDC-0941 led to approximately three-fold increases in perfusion, substantially reduced hypoxia and vascular normalization by histology. Significantly increased amounts of doxorubicin were delivered to the tumors correlating with synergistic tumor growth delay. The GDC-0941 itself had no effect on tumor growth.Conclusion: Inhibition of PI3K led to vascular normalization and improved delivery of a chemotherapeutic agent. This study highlights the importance of the microvascular effects of some novel oncogenic signaling inhibitors and the need to take those changes into account in the design of clinical trials many of which use combinations of chemotherapeutic agents. Clin Cancer Res; 18(1); 161–9. ©2011 AACR.

Supplementary Figures 1-9 from Tumor Vascular Changes Mediated by Inhibition of Oncogenic Signaling

Introduction: Up to 30% of patients (pts) aged ≥75 years do not receive standard chemoimmunotherapy (CIT) as first-line (1L) treatment for diffuse large B-cell lymphoma (DLBCL) due to concerns about frailty and comorbidities. Poor outcomes are commonly reported for elderly/unfit pts with 1L DLBCL who receive no treatment, reduced-dose R-CHOP or other therapies such as R-CVP and R-bendamustine (Morrison, et al. J Geriatr Oncol 2020); less toxic, efficacious alternatives to full-dose CIT are needed. Mosunetuzumab (Mosun) is a full-length, fully humanized IgG1 CD20/CD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. Single-agent Mosun has shown promising efficacy (including durable complete responses [CRs]) and tolerable safety in relapsed/refractory DLBCL pts in an ongoing Phase I study (GO29781; NCT02500407; Bartlett, et al. ASCO 2019, Schuster, et al. ASH 2019). Here we present early clinical data with Mosun as 1L therapy for elderly/unfit pts with DLBCL. Methods: GO40554 (NCT03677154) is a Phase I/II, open-label, multicenter study. We report data from Cohort B, designed to evaluate the safety, pharmacokinetics (PK) and preliminary efficacy of Mosun in pts with 1L DLBCL who are unable to tolerate full-dose CIT. Two safety evaluation cohorts were planned to receive Mosun at 13.5mg and 30mg, followed by an expansion phase. No safety concerns emerged following evaluation of the two safety cohorts. Eligible pts were aged ≥80 years or 60-79 years with impairment in ≥1 activity of daily living (ADL) or instrumental ADL, or with impairment in cardiac, renal or liver function precluding the use of full-dose CIT. After optional pre-phase treatment with prednisone with or without vincristine, pts received Mosun intravenously with step-up dosing on Day (D) 1, 8 and 15 of Cycle (C) 1, followed by a fixed dose on D1 of each subsequent 21-day cycle. Interim response assessment (IRA) occurred after C4 and primary response assessment (PRA) occurred after C8, with an option to continue up to maximum 17 cycles in case of partial remission (PR) following PRA. Results: As of May 27, 2020, 19 pts in Cohort B had received Mosun (1mg [C1 D1]/2mg [C1 D8]/13.5mg [C1 D15 onwards], n=8; 1/2/30mg, n=11). Eight pts were enrolled in the 13.5mg safety evaluation cohort and 11 enrolled in the 30mg safety cohort and expansion (7+4 respectively). Median age was 84 (range: 67-100) years, 14 (74%) pts were women, 10 (53%) had Ann Arbor stage III-IV and 17 (90%) had an IPI score ≥2. Median Mosun cycles received was 6 (range: 2-9; one pt in PR continued treatment). Among 19 pts, 16 (84%) had ≥1 adverse event (AE), 13 (68%) had ≥1 AE related to Mosun and 7 (37%) experienced a Grade (Gr) 3-4 AE, of which 4 were related to Mosun. No fatal AEs were observed. The most common (>10%) treatment-emergent AEs were cytokine release syndrome (CRS; n=9, 47%), rash (n=4, 21%), neutropenia, nausea, decreased appetite, dry mouth, fatigue, pain and muscle spasms (all n=2, 11%). All CRS events were Gr 1 by ASTCT consensus criteria (Lee, et al. Biol Blood Marrow Transplant 2019); no pts experienced hypotension, hypoxia or required tocilizumab or steroid treatment. No severe (Gr ≥3) neurologic AEs were observed. Gr 2 (ICAN) neurotoxicity was observed in one (5%) pt on C1D2 with symptoms of inability to answer questions, drowsiness, weakness and somnolence, combined with Gr 1 CRS (fever and tachycardia). The event resolved after 2 days and was considered related to Mosun. Eight (42%) pts discontinued Mosun early due to progressive disease (PD) between C2-C6. No pts discontinued Mosun due to an AE. Among all treated pts, the overall response rate was 58% (11/19) and CR rate was 42% (8/19). At Mosun dose 13.5mg, 3/8 pts (38%) achieved a CR, 2 (25%) had a PR and 3 (38%) had PD at the PRA. At Mosun dose 30mg, response was available at IRA: 5/11 pts (45.5%) achieved a CR, 1 (9%) had a PR and 5 (45.5%) had PD. Of the 8 pts with PD (from both dosing cohorts), 5 have received salvage therapy post progression. Figure 1 shows a durable response of almost a year for the first responder. Correlative studies of T-cell response by flow cytometry and cytokine expression, and PK analyses are ongoing and will be provided. Conclusions: Early clinical data indicate that single-agent Mosun confers notable efficacy and remarkable tolerability for previously untreated elderly/unfit DLBCL pts. Mosun is a promising chemotherapy-free regimen for patients who otherwise have limited options. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech, Inc.: Research Funding. Avigdor:Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. Babu:Amgen: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Fort Wayne Medical Oncology & Hematology: Current Employment, Current equity holder in publicly-traded company; Lilly: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Sanofi: Research Funding; Janssen Oncology: Research Funding; Lutheran Hospital: Other; Bayer: Honoraria; AstraZeneca: Consultancy, Honoraria; AstraZeneca/MedImmune: Research Funding; Boehringer Ingelheim: Consultancy; Alexion Pharmaceuticals: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Argenx: Consultancy, Research Funding; Novartis: Research Funding; Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; Syndax: Research Funding; Nektar: Research Funding; Merck: Research Funding; AbbVie: Research Funding; TG Therapeutics: Research Funding. Levi:Abbvie Inc: Consultancy, Research Funding. Abadi:Abbvie Inc: Research Funding; Roche, Gilead, Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Holmes:Texas Oncology PA: Current Employment; Gilead/Kite, Celgene/Juno, Rigel, Karyopharm, Janssen, Dova: Consultancy; Gilead/Kite, Novartis, Autolus, Celgene/Juno/bluebird, Genentech, Inc., Rigel, Janssen, Unum, ADC Therapeutics, Seattle Genetics, Incyte, Verastem: Research Funding; Kite, Karyopharm, Seattle Genetics, Rigel, Dova: Speakers Bureau. McKinney:UNUM, Molecular Templates, Incyte, Beigene, Denovo Biopharma, Pharmacyclics, Nordic Nanovector, BMS, Genentech, Inc., Celgene: Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Kite/Gilead, Seattle Genetics, Molecular Templates, BTG, Pharmacyclics, Verastem, Genentech, Inc., Celgene: Consultancy. McCord:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Xie:F. Hoffmann-La Roche: Current Employment. Chen:Janssen Pharmaceuticals: Current equity holder in publicly-traded company; Bristol-Myer Squibb: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Sarouei:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Qayum:F. Hoffmann-La Roche: Current Employment. O'Hear:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Sellam:F. Hoffmann-La Roche: Current Employment. Eradat:UCLA Medical Center, David Geffen school of Medicine at UCLA: Current Employment; Genentech, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; F. Hoffmann-La Roche: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astrazeneca, Atara, Kite, Juno, Acerta, BeiGene, Celgene: Research Funding. OffLabel Disclosure: Mosunetuzumab (RG7828; CD20-TDB) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

Context Mosun, a full-length, humanized, IgG1 CD20×CD3 bispecific antibody, demonstrated efficacy/safety in relapsed/refractory DLBCL (NCT02500407; Schuster, et al. ASH 2019). The phase I/II multicenter GO40554 (NCT03677154) study showed similar results for elderly/unfit patients with first-line DLBCL intolerant of full-dose chemoimmunotherapy (CIT) (Olszewski, et al. ASH 2020). Objective To describe updated GO40554 study data. Methods Two safety-evaluation cohorts were assessed (Mosun 13.5 mg and 30 mg), then a 30 mg expansion phase. Patients were aged ≥80 years; 60–79 years with impairment in ≥1 activity of daily living (ADL); instrumental ADL; or impaired cardiac, renal, or liver function. Patients received optional pre-treatment with prednisone (+/– vincristine), then intravenous mosun in step-up doses on days (D)1 (1 mg), 8 (2 mg), and 15 (full-dose: 13.5/30 mg) of cycle (C)1, and full (C1D15) dose on D1 of each 21-day cycle for eight cycles, continuing for ≤17 cycles. Results As of January 15, 2021, 40 patients received mosun (13.5 mg safety cohort, n=8; 30 mg safety cohort, n=7; 30 mg expansion, n=25). Median age: 84 (range 67–100) years; 50% with Ann Arbor Stage III–IV, 80% with IPI score ≥2. Of 40 treated patients, 27 (67.5%) had ≥1 mosun-related adverse event (AE); 15 (37.5%) had a grade 3–4 AE. Most common treatment-emergent AE: cytokine release syndrome (CRS; n=9, 22.5%); five patients had neutropenia (12.5%). Six (15%) patients had grade 1 CRS per ASTCT (Lee, et al. Biol Blood Marrow Transplant 2019); three (7.5%) had grade 2 CRS, all managed with supportive care, fluids for hypotension, steroids, or low-flow oxygen, as required (no tocilizumab, vasopressors, high-flow oxygen, or intensive care). 14 (35%) patients discontinued due to progressive disease (PD). Overall response rate for efficacy-evaluable patients (n=31): 67.7%; complete response (CR) rate: 41.9%. Responses with 13.5 mg mosun: CR: 37.5%; PR: 37.5%; PD: 25%; with 30 mg mosun: CR: 43.5%; PR: 21.7%; stable disease/PD: 34.8%. Four durable responses were observed ≥12 months from start of therapy in 13 patients with CR (11 ongoing). Conclusions Mosun showed promising efficacy, including durable responses, and tolerable safety for elderly/unfit patients with 1L DLBCL; it should be further evaluated as a chemotherapy-free backbone for patients unable to tolerate standard CIT.

Background: Over a third of pts with 1L DLBCL do not respond to, or relapse after, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP; [Sarkozy and Sehn. Ann Lymphoma 2019]). Despite recent advances, pts with R/R NHL have limited curative options. Glofitamab (Glofit) is a novel, T-cell-engaging bispecific antibody with a 2:1 molecular configuration that allows bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells. Unlike other CD20xCD3 bispecific antibodies, this format uniquely enables combination with anti-CD20 antibodies, including rituximab. Glofit monotherapy induces high response rates in R/R B-cell NHL (Hutchings et al. J Clin Oncol 2021). We present results of the ongoing NP40126 study (NCT03467373), designed to assess the feasibility and safety of Glofit + R-CHOP in R/R NHL (dose-escalation phase) and 1L DLBCL (safety run-in phase). Methods: R/R NHL dose-escalation: Pts (Eastern Cooperative Oncology Group performance status [ECOG PS] 0-2) received increasing Glofit doses in separate cohorts (70µg, 1800µg, 10mg and 30mg) plus standard R-CHOP for 6-8 cycles (each 21-day). To mitigate CRS risk, R- or obinutuzumab (G)-CHOP was given in Cycle (C)1, with the aim of tumor debulking. Glofit was given from C2 onwards. For 70µg and 1800µg cohorts, fixed-dose Glofit was given on C2 Day (D)8 and onwards. For 10mg and 30mg cohorts, step-up dosing was used to further mitigate CRS risk (2.5mg C2D8, 10mg C2D15, target dose C3D8 and onwards). Optional Glofit maintenance was permitted (every 2 months for 1L DLBCL safety run-in: Pts (ECOG PS 0-3) received Glofit 30mg plus standard R-CHOP for 6-8 cycles (each 21-day). Pts received R-CHOP in C1; Glofit step-up dosing began in C2 (2.5mg C2D8, 10mg C2D15, 30mg C3D8 and onwards). Response rates were assessed by PET-CT (Lugano criteria; [Cheson et al. J Clin Oncol 2014]). CRS events were graded by ASTCT criteria [Lee et al. Biol Blood Marrow Transplant 2019]. Results: R/R NHL dose-escalation: At data cut-off (June 10, 2021), 31 pts (23 follicular lymphoma [FL]; 6 transformed FL; 1 marginal-zone lymphoma; 1 mantle-cell lymphoma) had received Glofit with R/G-CHOP. Median age was 62 years, median prior lines of therapy was 2 (range: 1-5). In efficacy-evaluable pts (n=31), after a median 9.0 months' (range: 0-29) follow-up, the overall response rate (ORR) was 90% (n=28) and complete response rate (CRR) was 77% (n=24). Median duration of response was not reached. The Figure shows change in tumor size. Grade (Gr) ≥3 adverse events (AEs) occurred in 28 (90%) pts, serious AEs in 21 (68%) pts and CRS in 17 (55%) pts (mostly low grade; majority after the first 2.5mg Glofit dose; Table). One (3%) pt had a Gr 5 AE (COVID-19 pneumonia not related to study treatment). AEs led to Glofit dose modification/interruption in 2 (6%) pts and Glofit withdrawal in 1 (3%) pt. Neurologic AEs (NAEs) occurred in 20 (65%) pts: Gr 1-2 (16 pts, 52%); Gr 3 (4 pts, 13%). Immune effector cell-associated neurotoxicity syndrome (ICANS)-like AEs were uncommon; a serious AE was reported in 1 pt only (Gr 3 epilepsy during the maintenance phase; resolved in 3 days). Neutropenia occurred in 24 (77%) pts. Median dose intensity was 100% for all R-CHOP components. 1L DLBCL safety run-in: At data cut-off, 13 pts were enrolled (safety population); of these, 4 pts received Glofit 30mg with R-CHOP and were efficacy-evaluable. Median age was 68 years, all pts had Ann Arbor Stage 3/4 disease. At interim assessment (C3), CRR was 100% (4/4). Of 13 pts, 1 (8%) had a CRS event (Gr 1 with fever only) after the first 2.5mg Glofit dose; no other CRS events observed. Gr ≥3 AEs occurred in 8 (62%) pts and Gr ≥3 AEs related to Glofit in 1 (8%) pt only. One (8%) pt had a serious AE and 1 (8%) pt had a Gr 5 AE (infusion-related reaction related to rituximab on C1D1). No AEs led to Glofit or R-CHOP dose interruptions. NAEs occurred in 3 (23%) pts (all Gr 1-2; none were ICANS-like). Neutropenia occurred in 6 (46%) pts. Median dose intensity was 100% for all R-CHOP components. Conclusions: Initial data show that Glofit + R-CHOP has tolerable safety in R/R NHL and 1L DLBCL. R-CHOP dose intensity was maintained in all pts. The very low CRS rate and no neurotoxicity in 1L DLBCL may render Glofit particularly suitable for the outpatient setting without the need for hospitalization. Updated data, including end-of-treatment responses from the 1L DLBCL safety run-in phase, will be presented. Figure 1 Figure 1. Disclosures Ghosh: Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Genentech: Research Funding. Townsend: Celgene (Bristol-Myers Squibb): Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Dickinson: Amgen: Honoraria; Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau. Topp: Celgene: Consultancy, Research Funding; Janssen: Consultancy; Universitatklinikum Wurzburg: Current Employment; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy, Research Funding; Gilead: Research Funding; Regeneron: Consultancy, Research Funding; Macrogeniecs: Research Funding; Amgen: Consultancy, Research Funding. Santoro: Sandoz: Speakers Bureau; Eli-Lilly: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Speakers Bureau; Roche: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; Sanofi: Consultancy; Arqule: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Crump: Novartis: Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Research Funding; Roche: Research Funding. Morschhauser: Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Mehta: Kite/Gilead; Roche-Genetech; Celgene/BMS;Oncotartis; Innate Pharmaceuticals; Seattle Genetics;Incyte; Takeda; Fortyseven Inc/Gilead; TG Therapeutics;Merck; Juno Pharmaceuticals/BMS: Research Funding; Seattle Genetics; Incyte; TG Therapeutics: Consultancy; Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Panchal: F. Hoffmann-La Roche Ltd: Current Employment. Wu: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Barrett: Roche Products Ltd: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Qayum: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Hutchings: Novartis: Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Glofitamab is a full-length, humanized immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent. Rituximab (Rituxan) is a CD20-directed cytolytic antibody indicated for the treatment of adult pts with: relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL as a single agent; previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy (chemo) and, in pts achieving a CR or PR to a rituximab product in combination with chemo, as single-agent maintenance therapy; non-progressing (including stable disease), low-grade, CD20 positive, B-cell NHL as a single agent after first-line CVP chemo; previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP or other anthracycline-based chemo regimens; previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide.

Aim: Despite long-term responses to first-line immunochemotherapy, many patients with diffuse large B-cell lymphoma (DLBCL) have relapsed/refractory disease. Second-line treatment options are available. However, a large proportion of patients are ineligible for transplantation/intensive therapy. Patients & methods: This observational study of 702 patients in the USA, who used second-line therapies for relapsed/refractory DLBCL, evaluated treatment patterns and overall survival (OS). The study focused on the OS outcome of patients receiving second-line rituximab–bendamustine or rituximab–gemcitabine–oxaliplatin. Results & conclusion: Rituximab–bendamustine and rituximab–gemcitabine–oxaliplatin were received by 4.6 and 1.4% of patients, respectively (N = 42/702). Median and 1-year OS rates were similar between regimens. Many of the 200 different treatment regimens observed in second line were modified versions of National Comprehensive Cancer Network regimens.

Clinical trials have identified peripheral oedema (PO) as an adverse event of vildagliptin (an oral anti-diabetic drug [OAD]). A post-marketing study (PMS) was conducted to advance the understanding of vildagliptin use and particular safety concerns identified within the risk-management plan. PMS objectives included comparing the hazards between vildagliptin monotherapy and combination therapy for selected a priori identified risks, including PO. This study was a per-protocol supplementary analysis to investigate the pattern of onset and effect of vildagliptin combination therapy on PO risk. The PMS used an observational cohort design. OAD exposure, selected risk factors and outcome data were collected from general practitioners in England regarding vildagliptin users for the 6-month period after starting treatment. Data analysis comprised univariate case/non-case analysis, time-to-onset analysis and Cox proportional hazard models to estimate hazard ratios (HR) of PO adjusting for selected patients’ baseline characteristics. The study cohort included 4828 patients (median age 63 years; interquartile range [IQR] 54–71), 2692 of whom were male (55.8 %). The crude cumulative hazard of PO was 19.09 cases (95 % confidence interval [CI] 13.54–26.10) per 1000 person-years; 50 % of cases occurred during the first 34 days of treatment. A significantly faster time to PO onset was observed in patients prescribed concomitant sulfonylureas versus other treatment combinations (log rank test [LRT] p = 0.0365); in patients with a prior history of PO (LRT p

This paper reports a method that aims to quantify the changes of tumour vascular structure as a result of drug treatment. The measures we have investigated to date include: vessel radii, inter-branch lengths, tortuosity and branch angles. We show that the distribution of vessel radii is better modelled as a gamma distribution as opposed to the log-normal distribution asserted by other researchers. We propose a new metric based on multiple linear regression to measure vascular tortuosity. We report statistical analyses which confirm that (as expected), at different significance levels, all the drugs we have tested (FTI, Iressa, Nelfinavir and PI-103) have positive effects in improving a tumour's vascular network. In each case, the changes are quantified.

Introduction: DLBCL is the most common subtype of non-Hodgkin lymphoma. R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) is established as the standard of care for patients (pts) with previously untreated DLBCL, but ~40% of pts will eventually relapse. For relapsed/refractory pts who are ineligible for transplant, clinical guidelines propose a broad spectrum of therapeutic options. However, little is known about treatment patterns and outcomes associated with 2L therapy in routine practice, particularly for pts less suitable for intensive therapy. Therefore, using real-world data, we evaluated 2L treatment patterns in DLBCL pts and overall survival (OS) in those pts who received 2L R-Benda or R-GemOx. We focused on these 2 treatments as they are typically used in the non-transplant setting in pts less suitable for aggressive therapy, and can typically be administered in an outpatient setting. Methods: DLBCL pts receiving care from the US Veterans Health Administration were identified through their electronic medical records and raw oncology domain. Pts diagnosed with DLBCL (and no prior other types of malignancies) between 2004-2016, with ≥1-month follow-up and who received 2L treatment were included. OS (defined as time from the start of 2L therapy until death) was analyzed in pts who received 2L R-Benda or R-GemOx using the Kaplan-Meier method. Surviving pts were censored at data cutoff (December 31, 2017). Univariate and multivariate Cox regression analyses were undertaken to assess the impact of 2L treatment (in particular, R-GemOx vs R-Benda) on OS. Results: A total of 2600 DLBCL pts were identified: 2039 received 1L and 702 received 1L and 2L therapy. Among the 702 pts treated with 2L therapy, regimens included R-ICE (n=77; 11.0%), R-CHOP (n=75; 10.7%), rituximab monotherapy (n=34; 4.8%), R-Benda (n=32; 4.6%), methotrexate (n=24; 3.4%), R-ESHAP (n=23; 3.3%), R-DHAP/R-EPOCH/R-GDP (n=18; 2.6%), rituximab plus cyclophosphamide-doxorubicin-vinblastine-vincristine (n=14; 2.0%), R-CVP (n=11; 1.6%), rituximab plus cyclophosphamide-etoposide-vincristine (n=11; 1.6%), and R-GemOx (n=10; 1.4%). Of the remaining pts, 267 (38.0%) received regimens with agent(s) included in the NCCN guidelines, while 106 (15.1%) received regimens with at least 1 agent not guideline-recommended. Baseline characteristics for pts treated with 2L R-Benda (n=32) or R-GemOx (n=10) are shown in Table 1. There was an imbalance between the 2 cohorts with regard to race, number of involved lymph nodes, B symptoms, Charlson Comorbidity Index score, and abnormal lactate dehydrogenase results. After 24 deaths in the R-Benda cohort and 7 deaths in the R-GemOx cohort, median OS was estimated at 11 and 13 months, respectively (Figure 1). Median follow-up time after start of 2L treatment was 11.3 and 11.7 months, respectively. The Kaplan-Meier curves of the 2 cohorts overlapped at multiple timepoints during follow-up. Respective 1-year OS rates (95% confidence interval [CI]) with R-Benda and R-GemOx were 50.0% (31.9%, 65.7%) and 60.0% (25.3%, 82.7%). Compared with R-Benda, R-GemOx did not significantly predict longer OS in either the univariate (hazard ratio [HR]: 0.94; 95% CI: 0.41, 2.19; p=0.893) or multivariate (HR: 1.07; 95% CI: 0.46, 2.50; p=0.873) analyses. Conclusions: This real-world study highlights the diversity of 2L treatment regimens used in DLBCL pts. There was no apparent difference in OS between R-Benda- and R-GemOx-treated pts and, with a median OS of approximately 1 year after 2L initiation with either regimen, there is clearly an unmet need in this setting. The main limitation of the study relates to the small sample size of each treatment cohort. Further research using other real-world data sources is warranted. Disclosures Ionescu-Ittu: Analysis Group, Inc.: Employment; F. Hoffman-La Roche Ltd: Consultancy, Other: I am an employee of Analysis Group, Inc., which received consulting fees from Roche for the conduct of this study. Shang:F. Hoffmann-La Roche Ltd.: Employment, Other: Ownership interests non-PLC. Guérin:F. Hoffman-La Roche Ltd: Other: I am an employee of Analysis Group, Inc., which received consulting fees from Roche for the conduct of this study; Analysis Group, Inc.: Employment. Shi:F. Hoffman-La Roche Ltd: Research Funding; Bravo4Health: Other: Ownership interests non-PLC; Genentech: Research Funding; Chiasma: Research Funding; Intuitive Surgical: Consultancy. Shi:F. Hoffman-La Roche Ltd: Other: I am an employee of Analysis Group, Inc., which received consulting fees from Roche for the conduct of this study; Analysis Group, Inc.: Employment. Qayum:F. Hoffmann-La Roche Ltd: Employment.

Many inhibitors of the epidermal growth factor receptor (EGFR)-RAS-phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway are in clinical use or under development for cancer therapy. Here, we show that treatment of mice bearing human tumor xenografts with inhibitors that block EGFR, RAS, PI3K, or AKT resulted in prolonged and durable enhancement of tumor vascular flow, perfusion, and decreased tumor hypoxia. The vessels in the treated tumors had decreased tortuosity and increased internodal length accounting for the functional alterations. Inhibition of tumor growth cannot account for these results, as the drugs were given at doses that did not alter tumor growth. The tumor cell itself was an essential target, as HT1080 tumors that lack EGFR did not respond to an EGFR inhibitor but did respond with vascular alterations to RAS or PI3K inhibition. We extended these observations to spontaneously arising tumors in MMTV-neu mice. These tumors also responded to PI3K inhibition with decreased tumor hypoxia, increased vascular flow, and morphologic alterations of their vessels, including increased vascular maturity and acquisition of pericyte markers. These changes are similar to the vascular normalization that has been described after the antiangiogenic treatment of xenografts. One difficulty in the use of vascular normalization as a therapeutic strategy has been its limited duration. In contrast, blocking tumor cell RAS-PI3K-AKT signaling led to persistent vascular changes that might be incorporated into clinical strategies based on improvement of vascular flow or decreased hypoxia. These results indicate that vascular alterations must be considered as a consequence of signaling inhibition in cancer therapy. [Cancer Res 2009;69(15):6347–54]