Abstract: Introduction: Natural killer (NK) cells are key elements of the innate immune system. Obinutuzumab (GA101; G) is an anti-CD20 monoclonal antibody with enhanced direct cell death activity and antibody-dependent cellular cytotoxicity (ADCC) vs rituximab (R). Upon binding CD20-bound G/R, NK cells are activated and attack the target cell. Therefore, low pre-treatment NK cell count (NKCC) may be associated with worse outcomes in G/R-treated patients (pts). This exploratory post hoc analysis evaluated the prognostic impact of baseline (BL) NKCC in FL pts treated with G/R plus chemo in the Phase 3 GALLIUM trial (NCT01332968) and DLBCL pts treated with G/R plus CHOP in the Phase 3 GOYA trial (NCT01287741). Methods: BL peripheral blood (PB) NKCCs, assessed by flow cytometry (CD3-CD56+CD16+ cells; normal range [central lab]: 95-640 cells/µL), were available in 1064/1202 (88.6%) FL pts and 1287/1418 (90.8%) DLBCL pts. Cell-of-origin (COO) was determined in 933/1418 DLBCL pts using the Nanostring Research Use Only Lymphoma Subtyping Test (LST). COO and BL NKCC were available in 857/1418 pts. Whole transcriptome gene expression was analyzed using TruSeq RNA sequencing in tumor tissue from 552/1418 DLBCL pts. A 57-gene signature designed to reflect NK cell tumor infiltration was applied to RNA sequencing data from 552 pts; median score was used to define high/low subgroups. Kaplan-Meier methodology was used to estimate progression-free (PFS) and overall survival (OS), and a Cox regression univariate model was used to estimate corresponding HR and CI. The relative importance of BL variables (NKCC, gender, geographic region, treatment arm, chemo backbone/no. of planned chemo cycles, FLIPI/IPI, extranodal/bone marrow involvement, sum of products of diameter, Ann Arbor stage) was evaluated using multivariate (MV) Cox regression models with a stepwise approach. Results: Median (range) BL NKCCs were 220 cells/μL (0-3300) in FL and 200 cells/μL (0-1900) in DLBCL pts. Overall, 108/1064 (10.2%) FL pts and 255/1287 (19.8%) DLBCL pts had low BL NKCC ( & lt;100 cells/μL). By COO subtype, 83/485 (17.1%) germinal center B-cell-like (GCB), 37/140 (26.4%) unclassified, and 54/232 (23.3%) activated B-cell-like (ABC) DLBCL pts had low BL NKCC. BL disease characteristics of pts with low vs normal NKCCs are shown in Table 1. Low BL NKCC was associated with advanced disease. On univariate analysis low BL NKCC was associated with shorter PFS in FL (HR 1.57, 95% CI 1.10-2.25, p=0.01; 3-yr PFS 71.6% vs 80.1%) and DLBCL (HR 1.36, 95% CI 1.07-1.72, p=0.01; 3-yr PFS 62.8% vs 70.0%; Figure 1), and shorter OS in FL (HR 2.58, 95% CI 1.51-4.42, p=0.0003; 3-yr OS 87.6% vs 94.3%). DLBCL pts with low NKCC had a trend to worse OS vs pts with normal NKCC (HR 1.35, 95% CI 1.00-1.82, p=0.052; 3-yr OS 77.6% vs 82.3%). On MV analysis, low BL NKCC was independently associated with PFS in FL (HR 1.48, 95% CI 1.02-2.14, p=0.04) and DLBCL (HR 1.36, 95% CI 1.01-1.83, p=0.04). The DLBCL result appeared to be driven by COO subtype, with the highest estimated HR in GCB (HR 1.58, 95% CI 1.0-2.5, p=0.05), and no effect in unclassified and ABC. Interestingly, in line with the enhanced ADCC of G, the impact of low BL NKCC on PFS was stronger in G-treated FL pts (HR 2.06, 95% CI 1.24-3.41, p & lt;0.01) vs R-treated pts (HR 1.19, 95% CI 0.71-1.99, p=0.5), while less pronounced in the GCB DLBCL subgroup (G-treated pts: HR 1.25, 95% CI 0.91-0.77, p=0.182; R-treated pts: HR 1.47, 95% CI 1.06-2.06, p=0.021; Figure 2). Although there was no correlation between PB NKCC and tumor NK cell gene expression among biomarker-evaluable pts in GOYA, low tumor NK cell gene expression was associated with shorter PFS in G-treated DLBCL pts (all COO subtypes; HR 1.95, 95% CI 1.2-3.1, p & lt;0.01), with a trend for low CD56 mRNA expression alone (as continuous variable) correlating with shorter PFS (p=0.043). Conclusions: In this largest prospective collection of PB NK cells to date in FL and DLBCL, substantial numbers of pts had reduced NKCCs at BL, which was associated with advanced disease. Univariate and MV analyses may suggest that low PB NKCC is independently associated with shorter PFS in FL and DLBCL and shorter OS in FL. Likewise, low NK cell gene expression in tumor tissue was associated with shorter PFS in G-treated DLBCL pts. Collectively, our results from this exploratory analysis indicate that the number of NK cells in PB and tumor tissue may impact clinical outcome of non-Hodgkin lymphoma pts treated with anti-CD20 antibodies. Disclosures Klanova: F. Hoffmann-La Roche Ltd: Employment, Other: GALLIUM and GOYA are sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial support, under the direction of Magdalena Klanova, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. Oestergaard: F. Hoffmann-La Roche Ltd: Employment. Trněný: Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Marcus: Celgene: Other: Support for meeting attendance ; Roche: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Sehn: Roche/Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Vitolo: Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bazeos: Roche: Other: • A year-long academic collaboration contract with Roche (no financial gain).. Goede: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau. Zeuner: Roche: Employment. Knapp: Roche: Employment. Sahin: Roche: Employment, Equity Ownership. Danesi: Roche: Employment. Bolen: Genentech: Employment, Equity Ownership. Robson: F. Hoffmann la Roche: Employment. Venstrom: Genentech, Inc.: Employment. Nielsen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership.

Abstract: The pathophysiology of writer's cramp, a task‐specific dystonia, remains unclear. The objective of this study was to investigate the basal ganglia circuit and the cerebellum during a complex motor sequence learning task carried out with the nonaffected hand in writer's cramp patients. Methods We applied structural and functional imaging in 22 writer's cramp patients and 28 matched controls using 3T MRI . With the asymptomatic left hand all participants learned a complex, sequential, five‐element sequence‐tapping task as accurately and quickly as possible. Functional imaging was measured during a repeated (15 times), fixed block design with tapping (30 sec) and rest (30 sec). Additionally, gray matter volume of the basal ganglia was analyzed using voxel‐based morphometry ( VBM ). Results While behavior was comparable between groups, after small volume correction the anterior part of the right putamen and the left globus pallidus exhibited reduced blood oxygen level‐dependent ( BOLD ) activity in patients during the sequential finger‐tapping task. VBM analysis showed larger gray matter volume bilateral in the posterior part of the putamen and globus pallidus. There were no group differences in the cerebellum. Conclusion The results indicate an impairment of anterior basal ganglia loops involved in producing complex sequential movements of the unaffected hand. These findings are in line with previous reports of reduced neuronal activity in the globus pallidus internus. Higher gray matter volume of the putamen and globus pallidus may stem from elevated activity of the direct pathway, which could reflect a compensatory phenomenon or a primary predisposition, that is, endophenotypic trait.

Abstract: 9047 Background: NTRK fusions, encoding for constitutively active oncogenic tropomyosin receptor kinase proteins, are present in many solid tumors, including NSCLC. As central nervous system (CNS) metastases are common in pts with advanced NSCLC, treatments with intracranial efficacy are needed. Entrectinib, a potent CNS-active tyrosine kinase inhibitor, has previously demonstrated efficacy in pts with NTRK-fp NSCLC in an integrated analysis of three phase I/II trials (ALKA-372-001 [EudraCT, 2012-000148–88], STARTRK-1 [NCT02097810] , STARTRK-2 [NCT02568267]); objective response rate (ORR) was 63.6% (14/22; data cutoff: August 31 2020). We present updated data for this cohort. Methods: Pts ≥18 years old with locally advanced/metastatic NTRK-fp tumors were enrolled and received 600 mg oral entrectinib until disease progression, toxicity, or death. At Week 4 and then every 8 weeks, tumour response was assessed by blinded independent central review (BICR) per RECIST v1.1. Co-primary endpoints were ORR and duration of response (DoR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy, and safety. Enrolment cutoff: July 2 2020; data cutoff: August 2 2021. Results: The efficacy-evaluable population included 31 pts with NTRK-fp NSCLC. Median age was 60.0 years (range 22–88); 26 pts (83.9%) had adenocarcinoma; 11 pts (35.5%) had ≥2 prior lines of systemic therapy; 18 pts (58.1%) were current or former smokers; 15 pts (48.4%) had investigator-assessed baseline CNS metastases. Median survival follow up was 21.8 months (95% CI 19.5–30.2). Entrectinib treatment showed efficacy in pts with NTRK-fp NSCLC, including those with baseline CNS metastases by investigator (Table). In pts with BICR-assessed CNS metastases, intracranial ORR was 60.0% (6/10; 95% CI 26.2–87.8), median intracranial DoR was not estimable (NE), and median intracranial PFS was 8.9 months (95% CI 5.6–NE). In the safety-evaluable population (N=35), most treatment-related adverse events (TRAEs) were Grade 1–2 and non-serious. TRAEs led to dose reduction, interruption and discontinuation in 31.4%, 28.6%, and 5.7% of pts, respectively, and no treatment-related deaths occurred. Conclusions: In line with previously reported data, treatment with entrectinib was associated with deep and durable systemic and intracranial responses in pts with advanced NTRK-fp NSCLC. Clinical trial information: EUCTR 2012-000148-88 , NCT02097810 , NCT02568267 . [Table: see text]

Abstract: 3099 Background: NTRK gene fusions, coding for chimeric TRK proteins, are oncogenic drivers in many solid tumors. In an integrated analysis of three phase 1/2 trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810] ; STARTRK-2 [NCT02568267]), entrectinib, a potent CNS-active TRK inhibitor, showed durable systemic and intracranial responses in pts with NTRK-fp solid tumors. We report updated data from a larger cohort with longer follow-up (clinical cutoff 2 Aug 2021). Methods: Pts with locally advanced/metastatic NTRK-fp solid tumors and ≥12 months’ follow-up from first tumor assessment were efficacy evaluable. The safety cohort also included pts from TAPISTRY (NCT04589845). Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every 8 weeks thereafter. Primary endpoints: objective response rate (ORR) and duration of response (DoR). Progression-free survival (PFS), overall survival (OS), intracranial (IC)-ORR and safety were also assessed. Results: The efficacy-evaluable cohort comprised 150 adults (vs 121 previously) with 17 different solid tumor types. Median age was 58.5 years; 91% of pts had ECOG PS 0–1 and 37% had received ≥2 prior lines of therapy. Median survival follow-up was 30.6 months. ORR was 61.3% (n = 92/150; 95% CI: 53.1–69.2), including 25 complete responses. Responses were observed in all tumor types with n 〉 1 (Table). Median DoR, PFS and OS were 20.0 months (95% CI 13.2–31.1), 13.8 months (95% CI 10.1–20.0), and 37.1 months (95% CI 27.2–not estimable [NE]), respectively. In pts with and without investigator-assessed baseline CNS metastases (n = 31 / n = 119), ORR was 61.3% (95% CI 42.2–78.2) and 61.3% (95% CI 52.0–70.1) respectively. IC-ORR was 69.2% (n = 9/13) in pts with BICR-assessed measurable CNS metastases; median IC-DoR was 17.2 months (7.4–NE). In the safety population (N = 235: all treated pts), most treatment-related adverse events (TRAEs) were grade 1/2 and not serious; the most frequent were dysgeusia (36.6%), diarrhea (29.8%) and weight increase (28.5%). TRAEs led to dose interruption, reduction and discontinuation in 32.8%, 24.3% and 7.2% of pts, respectively. Conclusions: In this updated analysis, entrectinib continued to demonstrate deep and durable responses and was well tolerated in pts with NTRK-fp solid tumors with or without baseline CNS metastases. Clinical trial information: STARTRK-2 [NCT02568267] . [Table: see text]

Abstract: The PRIMA study (ClinicalTrials.gov identifier: NCT00140582 ) established that 2 years of rituximab maintenance after first-line immunochemotherapy significantly improved progression-free survival (PFS) in patients with follicular lymphoma compared with observation. Here, we report the final PFS and overall survival (OS) results from the PRIMA study after 9 years of follow-up and provide a final overview of safety. METHODS Patients ( 〉 18 years of age) with previously untreated high–tumor-burden follicular lymphoma were nonrandomly assigned to receive one of three immunochemotherapy induction regimens. Responding patients were randomly assigned (stratified by induction regimen, response to induction treatment, treatment center, and geographic region) 1:1 to receive 2 years of rituximab maintenance (375 mg/m 2 , once every 8 weeks), starting 8 weeks after the last induction treatment, or observation (no additional treatment). All patients in the extended follow-up provided their written informed consent (data cutoff: December 31, 2016). RESULTS In total, 1,018 patients completed induction treatment and were randomly assigned to rituximab maintenance (n = 505) or observation (n = 513). Consent for the extended follow-up was provided by 607 patients (59.6%) of 1,018 (rituximab maintenance, n = 309; observation, n = 298). After data cutoff, median PFS was 10.5 years in the rituximab maintenance arm compared with 4.1 years in the observation arm (hazard ratio, 0.61; 95% CI, 0.52 to 0.73; P 〈 .001). No OS difference was seen in patients randomly assigned to rituximab maintenance or observation (hazard ratio, 1.04; 95% CI, 0.77 to 1.40; P = .7948); 10-year OS estimates were approximately 80% in both study arms. No new safety signals were observed. CONCLUSION Rituximab maintenance after induction immunochemotherapy provides a significant long-term PFS, but not OS, benefit over observation.

Abstract: Introduction: Evidence suggests that baseline 18fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography-derived parameters, such as metabolic tumor volume (MTV) and maximum standardized uptake value (SUVmax), may predict progression-free survival (PFS) in patients (pts) with follicular lymphoma (FL) treated with first-line R-CHOP immunochemotherapy. However, data from pts routinely treated with bendamustine or antibody maintenance are lacking, and several methods have been used to evaluate PET metrics for tumor burden in pts with lymphoma. This prospective exploratory analysis assessed the prognostic value of baseline MTV, total glycolytic activity (TLG), and SUVmax for PFS and overall survival (OS) in pts with FL treated with first-line obinutuzumab (GA101; G) or rituximab (R) plus chemotherapy (chemo) in the Phase III GALLIUM study (NCT01332968; Marcus et al. N Engl J Med 2017), using two published methods for measuring tumor burden. Methods: Pts ≥18 years with previously untreated FL (grade 1-3a) and advanced disease (Stage III/IV or Stage II with tumor diameter ≥7cm) requiring treatment were randomized 1:1 to receive 6-8 cycles of G (1000mg intravenous [IV] on days [D] 1, 8, and 15 of cycle [C] 1 and D1, C2-6 or 8) or R (375mg/m2 IV on D1) plus standard chemo (CHOP, bendamustine, or CVP). Responding pts received the same antibody as maintenance every 2 months for up to 2 years. After an early protocol amendment, PET imaging at baseline and end of induction (EOI) was mandatory in the first 170 pts and optional thereafter. Independent reviewers segmented FDG-avid tumors applying thresholds of I) standardized uptake value (SUV)max ≥2.5, and II) SUVmax ≥41% of lesional maximum SUV and a minimum volume of 1mL, using MIM software. Results were analyzed for the PET intent-to-treat population. MTV, TLG, and SUVmax were split into quartiles: Q1, 〈 25%; Q2, 25-49%; Q3, 50-74%; and Q4, 75-100%, based on their distribution in the available population. Investigator-assessed PFS and OS were estimated using Kaplan-Meier methods (data cut-off, February 12, 2018). Hazard ratios refer to stratified log-rank tests comparing Q2, Q3, and Q4 with Q1, adjusted for the randomization stratification factors FLIPI score and chemo regimen. Multivariable Cox analyses were also undertaken to investigate whether baseline MTV quartiles and other covariates were prognostic for PFS. Statistical significance at 0.05 was determined using the Wald test. Results: Of 1202 enrolled FL pts, 609 had a baseline PET scan and 521 had baseline PET scans available for all quantitative assessments by central review; 303 pts (58%) received bendamustine, 179 (34%) CHOP, and 39 (8%) CVP. After a median follow-up of 57 months, none of the 3 baseline PET parameters (MTV or TLG measured by either method or SUVmax) significantly predicted PFS (Table). Multivariable analysis, which included baseline pt and disease characteristics, confirmed that MTV did not predict PFS. Consistent with the primary analysis, receipt of G-chemo was an independent predictor of improved PFS. Conclusions: Contrary to previous reports, these prospective data from the Phase III GALLIUM study show that baseline quantitative PET metrics do not predict PFS or OS in FL pts receiving first-line immunochemotherapy (of whom the majority received bendamustine) followed by antibody maintenance treatment, irrespective of the measurement method applied. Conversely, a previously reported analysis from GALLIUM suggests that PET-complete metabolic response at EOI assessed using Lugano 2014 criteria is a strong predictor of long-term outcome in these pts. Table. Table. Disclosures Barrington: EPSRC: Research Funding; Department of Health (England): Research Funding; F.Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees; National Institute of Health Research: Research Funding; MRC: Research Funding; CRUK: Research Funding. Trotman:Janssen: Other: Unremunerated member of Ad Board, Research Funding; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding; Takeda: Other: Unremunerated member of Ad Board; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding. Sahin:Roche: Employment, Equity Ownership. Belada:Janssen-Cilag: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Research Funding; Roche: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Davies:Janssen: Consultancy, Honoraria; GSK: Research Funding; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Pfizer: Research Funding. MacEwan:Consultant Radiologist/ Nuc Med Physician: Consultancy. Owen:Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Honoraria, Research Funding; Merck: Honoraria; Janssen: Honoraria, Research Funding; Teva: Honoraria; AbbVie: Research Funding. Ptáčník:F. Hoffman-La Roche: Honoraria. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Marcus:Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy; F. Hoffman-La Roche: Other: Travel support and lecture fees. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Mattiello:Roche: Employment. Zeuner:F. Hoffman-La Roche: Employment, Equity Ownership. Meignan:F. Hoffman-La Roche Ltd: Honoraria.

Abstract: Introduction: Immunochemotherapy is standard of care treatment for previously untreated patients (pts) with advanced stage follicular lymphoma (FL). However, the majority of pts relapse, with around 20% relapsing within 2 years. Obinutuzumab (GA101; G) is a glycoengineered type II anti-CD20 monoclonal antibody (mAb) with increased antibody-dependent cell-mediated phagocytosis and cytotoxicity, and direct B-cell killing, compared with the type I mAb rituximab (R). The randomized Phase III GALLIUM study (NCT01332968) compared the efficacy and safety of G-chemotherapy (G-chemo) vs R-chemotherapy (R-chemo) in previously untreated pts with advanced stage FL. In the primary analysis (PA), a significant improvement in the primary study endpoint of investigator (INV)-assessed progression-free survival (PFS) was demonstrated with G-chemo relative to R-chemo after 34.5 months' median follow-up. Results for other time-to-event outcomes (including time-to-next treatment; TTNT) were supportive, and additional analyses demonstrated a higher rate of minimal residual disease, and a lower risk of disease progression within 24 months, in the G-chemo arm. Here we report the results from an updated analysis of time-to-event endpoints and safety in the GALLIUM study. Methods: In GALLIUM, enrolled pts were aged ≥18 years with previously untreated FL (grades 1-3a), Stage III/IV disease (or Stage II with bulky disease), and ECOG PS 0-2, and requiring treatment according to GELF criteria. Pts were randomized 1:1 to receive G 1000mg IV (days 1, 8 and 15 of cycle 1 and day 1 of subsequent cycles) or R 375mg/m2 IV (day 1 of each cycle) plus chemotherapy for 6 or 8 cycles, depending on the chemotherapy backbone (CHOP, CVP, or bendamustine). Chemotherapy backbone was a stratification factor and was chosen upfront by the participating centers. Pts with a complete or partial response at the end of induction received maintenance with the same antibody every 2 months for 2 years. The data cut-off for the current analysis was February 12, 2018. Results: In total, 1202 pts with FL were enrolled (G-chemo, n=601; R-chemo, n=601), with a median age of 59 years (46.8% male). After 57.3 months' median follow-up, a sustained and clinically meaningful improvement in INV-assessed PFS was observed with G-chemo relative to R-chemo (HR 0.73; 95% CI: 0.59, 0.90; p=0.0034; 4-year PFS rate: G-chemo, 78.1% [95% CI: 74.4%, 81.3%]; R-chemo, 67.2% [95% CI: 63.1%, 71.0%] ; Figure 1A). Since the PA, 114 new PFS events (57 in G-chemo and 57 in R-chemo) had occurred. Overall survival (OS) data, which remain immature, were comparable across treatment arms (HR 0.88; 95% CI: 0.61, 1.27; p=0.49; 4-year OS rate: G-chemo, 92.6% [95% CI: 90.1%, 94.4%]; R-chemo, 90.3% [95% CI: 87.6%, 92.5%] ; Figure 1B). A sustained benefit in favor of G-chemo was observed in TTNT (HR 0.70; 95% CI: 0.54, 0.90; p=0.0046; 4-year TTNT rate: G-chemo, 84.2% [95% CI: 80.9%, 86.9%]; R-chemo, 76.7% [95% CI: 73.1%, 80.0%] ; Figure 1C). Since the PA, 29 and 36 additional pts in the G- and R-chemo arms, respectively, had received new anti-lymphoma treatment. At cut-off, 54 (9.1%) pts in the G-chemo arm and 61 (10.2%) in the R-chemo arm had died. Common causes were disease progression (G-chemo, n=21 [3.5%]; R-chemo, n=28 [4.7%] ) and AEs (G-chemo, n=24 [4.0%]; R-chemo, n=24 [4.0%] ). The most common fatal AEs were infections (9 vs 4 pts, respectively) and new malignancies (5 vs 6 pts, respectively). Incidences of AEs of any grade were comparable across the G-chemo (99.8%) and R-chemo (99.5%) arms, although grade 3-5 AEs (79.2% vs 71.2%) and serious AEs (48.7% vs 42.2%) were more common in the G-chemo arm. AEs led to discontinuation in 16.3% of G-chemo pts and 14.6% of R-chemo pts. As in the PA, the incidence of grade 3-5 infections (22.2% vs 18.6%), grade 3-5 neutropenia (and associated complications reported as AEs, 48.4% vs 41.4 %), and grade 3-5 second malignancies (6.9% vs 4.4%) was numerically higher in pts receiving G-chemo than R-chemo. Conclusions: In line with the PA, the results from this updated analysis of the GALLIUM study, with a median follow-up of almost 5 years, reinforce that G-chemo provides clinically meaningful improvements in outcomes relative to R-chemo in previously untreated FL pts. OS data remain immature, with additional follow-up needed to draw conclusions. Safety data are consistent with those reported in the PA. Figure 1. Figure 1. Disclosures Townsend: Gilead: Consultancy; Roche: Consultancy. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding. Cartron:Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Consultancy, Honoraria. Cunningham:Roche pharmaceuticals: Research Funding. Dyer:Roche: Honoraria, Research Funding. Gribben:Medical Research Council: Research Funding; Acerta Pharma: Honoraria, Research Funding; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; TG Therapeutics: Honoraria; Abbvie: Honoraria; Wellcome Trust: Research Funding; Unum: Equity Ownership; Pharmacyclics: Honoraria; NIH: Research Funding; Cancer Research UK: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite: Honoraria. Hess:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; CTI: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Keller:BMS: Consultancy; Celgene: Research Funding; MSD: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy. Kneba:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Malladi:Roche: Membership on an entity's Board of Directors or advisory committees. Neidhart:Gilead: Consultancy; Roche: Consultancy, Other: Travel support and lecture fees. Rusconi:Celgene: Research Funding. Zhu:Beijing Cancer Hospital (Peking University Cancer Hospital): Employment. Catalani:Roche: Employment. Knapp:Roche: Employment. Zeuner:F. Hoffman-La Roche: Employment, Equity Ownership. Hiddemann:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marcus:Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy; F. Hoffman-La Roche: Other: Travel support and lecture fees.

Abstract: Natural killer (NK) cells are key effector cells for anti-CD20 monoclonal antibodies (mAb), such as obinutuzumab and rituximab. We assessed whether low pretreatment NK-cell count (NKCC) in peripheral blood or tumor tissue was associated with worse outcome in patients receiving antibody-based therapy. Patients and Methods: Baseline peripheral blood NKCC was assessed by flow cytometry (CD3−CD56+ and/or CD16+ cells) in 1,064 of 1,202 patients with follicular lymphoma treated with obinutuzumab or rituximab plus chemotherapy in the phase III GALLIUM trial (NCT01332968) and 1,287 of 1,418 patients with diffuse large B-cell lymphoma (DLBCL) treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP or R-CHOP) in the phase III GOYA trial (NCT01287741). The prognostic value of tumor NK-cell gene expression, as assessed by whole-transcriptome gene expression using TruSeq RNA sequencing, was also analyzed. The association of baseline variables, such as treatment arm, was evaluated using multivariate Cox regression models using a stepwise approach. Results: In this exploratory analysis, low baseline peripheral blood NKCC was associated with shorter progression-free survival (PFS) in both follicular lymphoma [hazard ratio (HR), 1.48; 95% confidence interval (CI), 1.02–2.14; P = 0.04] and DLBCL (HR, 1.36; 95% CI, 1.01–1.83; P = 0.04), and overall survival in follicular lymphoma (HR, 2.20; 95% CI, 1.26–3.86; P = 0.0058). Low tumor NK-cell gene expression was associated with shorter PFS in G-CHOP–treated patients with DLBCL (HR, 1.95; 95% CI, 1.22–3.15; P & lt; 0.01). Conclusions: These findings indicate that the number of NK cells in peripheral blood may affect the outcome of patients with B-cell non-Hodgkin lymphoma receiving anti-CD20–based immunochemotherapy.