Abstract: Background: Patients with follicular lymphoma (FL) have a heterogenous prognosis. Recently a simple score, the PRIMA-PI, was developed based on the PRIMA clinical trial (Bachy et al Blood. 2018). With only two factors (beta-2-microglobulin level & gt; 3 mg/L and bone marrow involvement), this index was at least as discriminatory as FLIPI on the training and validation cohorts. The validity of the PRIMA-PI was confirmed on Czech and German FL cohorts and a patient group from the Nordic Lymphoma Group. However, further validation is needed to confirm the use of PRIMA-PI in place of FLIPI for prognostic assessment. Indeed, in the era of new chemo-free treatments, it seems important to challenge the potency of traditional prognostic factors and scores. Recently, rituximab combined with lenalidomide (R2) was compared to conventional immunochemotherapy (R-chemo) in the phase III RELEVANCE trial. The aim of our study was to validate PRIMA-PI in the RELEVANCE trial cohort and compare its performance with FLIPI (Solal-Celigny et al. Blood. 2004) and FLIPI2 (Federico et al. JCO. 2009). A secondary objective was to evaluate potential differences in terms of prognostic bio-clinical parameters between the R2 and R-chemo arms. Methods: All patients with available data for FLIPI, FLIPI2, and PRIMA-PI from the intention to treat population of the RELEVANCE study were included in the analysis. PFS according to each prognostic score were assessed in the total population and by treatment arms. Data were not mature enough to compare OS distributions. Performance metrics (log-rank p value and Net Reclassification Improvement [NRI]) were calculated for each group to assess concordance and discriminating ability of each score. Results: Median follow-up time for the study was 38 months. Overall, 846 RELEVANCE patients were included in the analysis. Data were available for 845 patients for FLIPI score assessment, 832 for FLIPI2 and 807 for PRIMA-PI. Group repartition according to the FLIPI and the FLIPI2 were largely imbalanced compared with PRIMA-PI. FLIPI classified very few patients in the low risk group (15% LR) while 49% of the patients were at high risk (HR), and 36% were at intermediate risk (IR). Similarly, FLIPI2 risk categories were as follow: 8% LR, 50% IR, and 42% HR. On the contrary, PRIMA-PI divided the study population into three equal groups (33%, 33% and 34%). In the total population, FLIPI and PRIMA-PI were predictive of PFS (p=0.029 and p=0.004, respectively); FLIPI2 showed poor performance (p=0.094). PFS curves based on each score are shown in Figure 1. NRI index indicated that the PRIMA-PI yielded analogous segregation for PFS with FLIPI (NRI 0.16; 95% CI: -0.008, 0.318; Table 1). In the R-chemo arm, both FLIPI and PRIMA-PI could isolate different prognostic groups for PFS, whereas FLIPI2 could not. Conversely, none of the indices were able to significantly discriminate outcomes for patients treated with R2. Interestingly, analysis showed that some usual prognostic factors, especially those likely to reflect tumor burden such as beta-2 microglobulin and LDH, were not predictive for PFS in the R2 arm. In contrast, low albumin ( & lt;40 g/L) and low hemoglobin ( & lt;120 g/L) levels were significantly associated with worse PFS in the R2 arm (p=0.001, and p=0.023), but not in the R-chemo arm. Conclusion: For patients with FL treated upfront with immunochemotherapy, the PRIMA-PI is a valid scoring system that allows to segregate patients as efficiently as the FLIPI while using only two factors. These results confirm that the PRIMA-PI could substitute for the FLIPI for patients treated with upfront R-chemo. Athough our data have to be interpreted in light of the short median follow-up time, they also suggest that other clinical/biological parameters might be considered and new prognostic indexes established for patients treated with R2. Considering possible mechanisms of action of lenalidomide, prognostic factors related to the underlying patient's immunological status might be more predictive. Disclosures Fowler: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bachy:Roche: Consultancy; Janssen Cilag: Honoraria; Gilead Science: Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen Cilag: Other: Travel, accomodation, Expense. Feugier:abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Astra-Zeneca: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding. Palomba:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Noble Insights: Consultancy; Evelo: Other: Immediate family member, Equity Ownership; MSK (IP for Juno and Seres): Other: Immediate Family Member, Patents & Royalties - describe: intellectual property rights ; Hemedicus: Other: Immediate Family Member, Speakers Bureau ; Merck & Co Inc.: Other: Immediate Family Member, Consultancy (includes expert testimony); Seres Therapeutics: Other: Immediate Family Member, Equity Ownership and Membership on an entity's Board of Directors or advisory committees; STRAXIMM: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Other: Immediate Family Member, Membership on an entity's Board of Directors or advisory committees. Libby:Akcea: Consultancy; Alnylam: Consultancy; Abbvie: Consultancy; Pharmacyclics and Janssen: Consultancy. Casasnovas:Merck Sharp and Dohme: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Flinn:TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding. Haioun:Novartis: Honoraria; Janssen: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Servier: Honoraria; Takeda: Honoraria; Miltenyi: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Bartlett:Pharmacyclics: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Forty Seven: Research Funding; Bristol-Myers Squibb: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Genenetech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Janssen: Research Funding. Bouabdallah:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Brice:BMS: Honoraria; Millennium Takeda: Research Funding; Takeda France: Consultancy, Honoraria. Ribrag:Nanostring: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; ArgenX: Research Funding; Roche: Other: Travel, accommodations, and expenses ; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses ; MSD: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees. Le Gouill:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche-Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Martín:Teva: Research Funding; Gilead: Consultancy, Honoraria; Kiowa Kirin: Consultancy; Roche: Consultancy, Honoraria, Other: Travel Expenses; iQone: Consultancy; Servier: Honoraria, Other: Travel Expenses; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding. Lopez-Guillermo:Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Research Funding. Larouche:Bayer; Gilead Sciences; Merck; Roche: Research Funding. Ando:Eisai: Research Funding. Maria:Janssen Cilag: Consultancy, Other: Travel support; Gilead Sciences: Other: Travel support, Research Funding; Abbvie: Consultancy, Other: Travel support; Celgene: Consultancy; Roche: Consultancy, Other: Travel support. André:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding; Chugai: Research Funding; Celgene: Other: Travel grants, Research Funding. Sehn:Merck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Janssen-Ortho: Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Tobinai:Daiichi Sankyo: Consultancy, Honoraria; Eisai: Honoraria, Research Funding; Verastem: Honoraria; Mundi Pharma: Consultancy, Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Yakult: Honoraria; Janssen Pharmaceutical: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; HUYA Bioscience: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; AbbVie: Research Funding; Solasia: Honoraria; Meiji Seika: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria, Research Funding. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Delarue:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Salles:BMS: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Morschhauser:Bayer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; BMS: 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: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: For patients (pts) with relapsed indolent non-Hodgkin lymphoma (iNHL) who develop resistance to rituximab, treatment options are limited and the prognosis is poor. The open-label, randomized, Phase III GADOLIN (NCT01059630) study compared the efficacy and safety of obinutuzumab (GA101; G) plus bendamustine (B) induction, followed by G maintenance (G-B arm), with B induction (B arm; standard of care) in rituximab-refractory iNHL. The primary analysis in 396 pts (data cutoff: September 1, 2014; median observation time, 21.0 months) showed that Independent Review Committee (IRC)-assessed progression-free survival (PFS; primary endpoint) was significantly longer with G-B (median not reached [NR]) vs B (14.9 months), corresponding to a 45% reduction in risk of progression or death (hazard ratio [HR] , 0.55; 95% confidence interval [CI]: 0.40, 0.74; p=0.0001; Sehn et al. Lancet Oncol 2016). The safety profile of G-B was manageable. Here, we report the final analysis of efficacy and safety for GADOLIN (when safety follow-up for all pts had been completed [2 years' safety follow-up from last dose] ; data cutoff: November 30, 2018). Methods: Enrolled pts were aged ≥18 years with documented rituximab-refractory iNHL and an ECOG performance status of 0-2. Pts received either G 1000mg intravenously (i.v.) (Days [D] 1, 8, and 15 of Cycle [C] 1, and D1 of C2-6) plus B 90mg/m2/day i.v. (D1 and 2 of C1-6) or B monotherapy (120mg/m2/day i.v., D1 and 2 of C1-6) in 28-day cycles. Following induction, pts in the G-B arm without evidence of progression received G maintenance (1000mg i.v. every 2 months for 2 years or until disease progression). Final analysis endpoints included investigator (INV)-assessed PFS, overall survival (OS), time to new anti-lymphoma treatment (TTNT), and safety. The safety population included pts who received ≥1 dose of study treatment, excluding two pts crossing over to G-B during maintenance. Results: Of 413 iNHL pts in the ITT population (G-B, 204; B, 209), 335 (G-B, 164; B, 171) had follicular lymphoma (FL). Median (range) observation time was 57.5 (0.4-97.6) months for the G-B arm and 47.9 (0-100.9) months for the B arm (i.e. 27.6 and 35.6 months additional follow-up since the primary analysis). Median INV-assessed PFS was 25.8 months for the G-B arm vs 14.1 months for the B arm (HR, 0.57; 95% CI: 0.45, 0.73; p 〈 0.0001) in all iNHL pts (Figure 1A). Overall, fewer iNHL pts died in the G-B (84/204; 41.2%) than in the B (100/203; 49.3%) arm; median OS was 88.3 vs 65.6 months (HR, 0.77; 95% CI: 0.57, 1.03; p=0.0810; 23% risk reduction [Figure 1A]). Median TTNT was also longer with G-B vs B (38.2 vs 18.9 months, respectively [HR, 0.60; 95% CI: 0.47, 0.76] ). Results for FL pts were as follows: median PFS, 24.1 vs 13.7 months (HR, 0.51; 95% CI: 0.39, 0.67; p 〈 0.0001 [Figure 1B]); median OS, NR vs 60.3 months (HR, 0.71; 95% CI: 0.51, 0.98; p=0.0343); median TTNT, 33.6 vs 18.0 months (HR, 0.56; 95% CI: 0.43, 0.73). In the safety population (N=407; G-B, 204; B, 203), 149/204 (73.0%) of pts in the G-B arm and 134/203 (66.0%) in the B arm experienced grade ≥3 adverse events (AEs). Compared with B, grade ≥3 neutropenia (37.3% vs 30.0%) and grade ≥3 infusion-related reactions (11.3% vs 5.4%) were more frequent with G-B, and grade ≥3 thrombocytopenia (10.8% vs 15.8%) and anemia (7.4% vs 10.8%) were less frequent. The incidences of grade ≥3 infections (22.5% vs 19.2%) and grade ≥3 second malignancies (7.8% vs 5.9%) were similar between arms. The proportion of pts with serious AEs was 91/204 (44.6%) in the G-B arm and 76/203 (37.4%) in the B arm; fatal AEs were reported in 20/204 (9.8%) and 15/203 (7.4%) of pts, respectively. The most frequent AEs leading to death in the G-B vs B arms were infections (six vs seven pts, respectively) and second malignancies (eight vs four pts, respectively). Safety results in FL pts were comparable with all iNHL pts. Conclusions: Final analysis of the GADOLIN study showed that G-B was associated with a 43% reduction in the risk of progression or death compared with B in pts with rituximab-refractory iNHL and a 49% reduction in pts with FL, with a sustained and clinically relevant OS benefit in pts with FL. There were no new safety signals with longer follow-up. Acknowledgments: The GADOLIN study was sponsored by F. Hoffmann-La Roche Ltd. Third party medical writing assistance, under the direction of Laurie Sehn, was provided by Louise Profit of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche Ltd. Disclosures Sehn: TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Celgene: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Trněný:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy; Gilead Sciences: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria. Bouabdallah:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dueck:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Roche: Research Funding. Gribben:Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Lugtenburg:Celgene: Honoraria; Janssen-Cilag: Honoraria; Servier: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Roche: Honoraria, Research Funding, Speakers Bureau; Genmab: Honoraria. Salles:Epizyme: Consultancy, Honoraria; BMS: Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. Knapp:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Liu:Roche Pharma Development, Shanghai, China: Employment. Cheson:Seattle Genetics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding.

Abstract: Background: Treatment options for patients (pts) with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL) are limited. GADOLIN (NCT01059630) is an open-label, randomized, Phase 3 trial comparing the efficacy and safety of obinutuzumab (GA101; GAZYVA/GAZYVARO; G) plus bendamustine (B) induction, followed by G maintenance (G-B arm), with B induction (standard of care) in rituximab-refractory iNHL pts. In the primary analysis, which involved all pts enrolled as of September 1, 2014 (n=396; median observation time, 21.0 months [mo]), median Independent Review Committee (IRC)-assessed progression-free survival (PFS; primary endpoint) was longer in the G-B arm (194 pts; median not reached) than in the B arm (202 pts; 14.9 mo), with a 45% reduction in risk of progression or death (HR 0.55; 95% CI 0.40, 0.74; p=0.0001). Investigator (INV)-assessed PFS was also significantly longer in the G-B arm, but overall survival (OS) data were immature. Safety profiles were comparable. The most common grade ≥3 adverse events (AEs) were neutropenia, thrombocytopenia, anemia, and infusion-related reactions (IRRs). Seventeen additional pts were enrolled after the data cut-off for the primary analysis. Here, we report updated time-to-event and safety results from a planned analysis of all pts (n=413) using a data cut-off of April 1, 2016. Methods: Enrolled pts were aged ≥18 years (yrs) with documented rituximab-refractory iNHL and an ECOG performance status of 0-2. Pts received either G 1000mg i.v. (days [D] 1, 8, and 15 of cycle [C] 1, and D1 of C2-6) plus B 90mg/m2/day i.v. (D1 and 2 of C1-6), or B monotherapy (120mg/m2/day i.v., D1 and 2 of C1-6); each cycle was 28 days. Following induction, pts in the G-B arm without evidence of progression received G maintenance (1000mg i.v. every 2 mo for 2 yrs or until disease progression, whichever occurred first). In the current analysis, assessments included INV-assessed PFS, OS, time to new anti-lymphoma treatment (TTNT), and safety. Efficacy assessment was performed on the intent-to-treat (ITT) population. Safety analysis included all pts who received any study treatment, excluding 2 pts who crossed over to G-B during maintenance. Results: Of 413 iNHL pts in the ITT population (G-B, 204; B, 209), 335 (G-B, 164; B, 171) had FL. Baseline characteristics of the ITT population were balanced between arms. Median number of prior regimens was 2 in both arms (pts with ≤2 prior regimens: G-B, 80.4%; B, 77.5%). Most pts were refractory to their last regimen (G-B, 92.2%; B, 92.3%). After 31.8 mo median follow-up, median INV-assessed PFS was 25.8 mo in the G-B arm and 14.1 mo in the B arm; HR was 0.57 (95% CI 0.44, 0.73; p 〈 0.0001), i.e. a 43% reduction in risk of progression or death for G-B relative to B. Fewer pts died in the G-B arm (25.5%) than the B arm (34.9%), with a HR for OS of 0.67 (95% CI 0.47, 0.96; p=0.0269; risk reduction, 33%; Figure 1A); median OS was not reached for either arm. Results for FL pts were consistent with those for ITT pts (median PFS: 25.3 vs. 14.0 mo [HR 0.52; 95% CI 0.39, 0.69; p 〈 0.0001]; median OS: not reached vs. 53.9 mo [HR 0.58; 95% CI 0.39, 0.86; p=0.0061; Figure 1B] ). Median TTNT was also longer in the G-B arm than in the B arm (ITT pts: 40.8 vs. 19.4 mo, respectively [HR 0.59; 95% CI 0.45, 0.77]; FL pts: 33.6 vs. 18.0 mo, respectively [HR 0.57; 95% CI 0.43, 0.75] ). The overall safety profile of G-B remained consistent with results of the primary analysis. In the ITT population, there were more grade ≥3 AEs with G-B than with B (72.5% vs. 65.5%, respectively), notably neutropenia (34.8% vs. 27.1%) and IRRs (9.3% vs. 3.5%); grade ≥3 thrombocytopenia (10.8% vs. 15.8%) and anemia (7.4% vs. 10.8%) were less frequent in the G-B arm, while grade ≥3 infections (22.5 % vs. 19.2%) and secondary malignancies (5.9% vs. 5.4%) were reported with a similar incidence. Serious AEs were more frequent in the G-B arm (43.6% vs. 36.9%), but the incidence of grade 5 (fatal) AEs was similar (7.8% vs. 6.4%). Safety results in FL pts were comparable with those in all iNHL pts. Conclusions: Updated analysis of the GADOLIN study with ~10 mo additional follow-up confirms the previously reported PFS benefit of G-B over B in pts with rituximab-refractory iNHL, and demonstrates a significant improvement in OS in the G-B arm. No new safety signals were detected. Figure 1. OS results: A) ITT population; B) FL pts Figure 1. OS results: A) ITT population; B) FL pts Disclosures Cheson: Roche-Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astra Zeneca: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Teva: Research Funding. Trněný:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dueck:Roche: Research Funding; Celgene: Honoraria, Research Funding; Onyx: Research Funding; Lundbeck: Honoraria, Research Funding. Lugtenburg:Celgene: Consultancy; Mundipharma: Consultancy; Servier: Consultancy; Roche: Consultancy; Takeda: Consultancy. Salles:Mundipharma: Honoraria; Gilead: Honoraria, Research Funding; Roche/Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Fingerle-Rowson:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Wassner-Fritsch:elisabeth.wassner_fritsch@roche.com: Employment. Sehn:Roche/Genentech: Consultancy, Research Funding; Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Abbvie: Consultancy; Lundbeck: Consultancy.