Kostakoğlu, Lale

Background: Standard first-line treatment for patients diagnosed with diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen. Despite numerous efforts to improve on this regimen, in all comers and specifically in those with activated B-cell (ABC)-type DLBCL, results from large randomized studies have failed to show a significant clinical advantage above this standard. Recently, 2 large clinical trials in previously untreated DLBCL evaluated the combination of lenalidomide/R-CHOP (R2-CHOP) vs standard R-CHOP and demonstrated discordant results. We analyzed data from these trials to identify differences that may have impacted the disparate trial outcomes while identifying patient characteristics associated with benefit from the addition of lenalidomide across the trials. Methods: The 2 trials included in this evaluation are ROBUST, an international, randomized, double-blinded, placebo-controlled, phase III study of R2-CHOP vs placebo/R-CHOP, and the Intergroup ECOG-ACRIN 1412 (E1412) trial, a US-only, randomized, open-label, phase II study of R2-CHOP vs R-CHOP. Additional key study design differences included dosing, and subtype timing and inclusion (both studies used gene expression profiling [GEP] by NanoString). R-CHOP dosing differed only for prednisone, which was a flat 100 mg dose, d1-5 in ROBUST and 100 mg/m2, d1-5 in E1412. The lenalidomide dose and schedule varied between studies: 15 mg/d, d1-14/21 for ROBUST (210 mg/cycle) and 25 mg/d, d1-10/21 (250 mg/cycle) for E1412. ROBUST enrolled only patients prospectively identified with the ABC subtype, whereas E1412 enrolled all otherwise eligible patients and retrospectively evaluated for ABC-type with prespecified ABC-type accrual and power parameters. Both studies enrolled patients with IPI status ≥ 2, ECOG PS 0-2, and Ann Arbor stage II-IV (E1412 stage II with mass > 10 cm). The primary endpoint in both was progression-free survival (PFS; central review for ROBUST and investigator-assessed for E1412). Secondary endpoints included event-free survival (EFS; key for ROBUST), overall and complete response rates, overall survival (OS), and safety. Results: ROBUST enrolled 570 ABC patients and E1412 enrolled 280 GCB, ABC, and unclassified DLBCL patients. Patient profiles in both studies (ROBUST [ABC]/E1412 [all COO]) were similar in terms of median ages (65 y/66 y), male sex (58%/61%), and ECOG PS 1-2 (55%/63%). Patients in E1412 were more high risk: IPI 2 (42% ROBUST/34% E1412), IPI ≥ 3 (58%/66%), and Ann Arbor stage III/IV disease (87%/97%). Importantly, there was a notable difference in the time from patient diagnosis to treatment: median 31 days for ROBUST and 21 days (22% > 31 d) for E1412. Only 6% of patients in ROBUST were treated within 2 weeks of diagnosis vs 30% in E1412. At a median follow-up of ~2.5 y for both studies, E1412 met its primary endpoint of improvement in PFS with 34% reduction in the risk of PD/death (2-y PFS: 76% vs 70%) for all patients, but did not reach statistical significance in ABC-DLBCL patients for 2-y PFS (71% vs 61%) or 2-y OS (88% vs 76%). ROBUST showed no significant improvement in the primary PFS endpoint (2-y PFS: 67% vs 64%) or 2-y OS (79% vs 80%) in ABC patients. Subgroup analyses of PFS comparing R2-CHOP vs R-CHOP control within each study suggested that certain baseline factors favor the R2-CHOP arm, including: female sex, high IPI score (≥ 3), non-bulky disease (< 7 cm), and high Ann Arbor stage IV disease. Conclusion: While the ROBUST study design integrated state-of-the-art, real-time GEP to prospectively identify ABC-DLBCL patients with rapid lab turnaround time, cases of logistical delays in tissue submission for central analysis and staging procedures may have resulted in accrual of patients with lower-risk DLBCL and prolonged time from diagnosis to treatment. In contrast, E1412 retrospectively stratified patients by COO through GEP and was able to accrue higher-risk patients irrespective of COO within a shorter time from diagnosis to treatment, which among other differences (eg, smaller population size, study phase), could contribute to the improvement over R-CHOP control. Our comparative findings have significant implications for the design of future biomarker-driven trials and provide momentum for studies of novel combinations with R-CHOP in DLBCL. Further investigation into other factors, including dose intensity and their correlation with outcomes, will be presented. Disclosures Nowakowski: Celgene: Consultancy, Research Funding; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Bayer: Consultancy, Research Funding. Chiappella:Servier: Other: advisory board, Speakers Bureau; Roche: Speakers Bureau; Teva: Speakers Bureau; Celgene: Other: advisory board, Speakers Bureau; Janssen: Other: advisory board, Speakers Bureau. Hong:Dana Farber Cancer Institute: Employment; Merck: Consultancy. Scott:Roche/Genentech: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Amengual:Appia Pharmaceuticals: Research Funding; Epizyme: Speakers Bureau. Leonard:BeiGene: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; Celgene: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; ADC Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Miltenyi: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Karyopharm Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Merck: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; Bayer Corporation: Consultancy; Sandoz: Consultancy; MorphoSys: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy; Nordic Nanovector: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. Kostakoglu:F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Jurczak:Morphosys: Research Funding; Bayer: Research Funding; Roche: Research Funding; Incyte: Research Funding; Gilead: Research Funding; Celgene Corporation: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yamamoto:Bristol-Myers Squibb: Consultancy, Honoraria; Bayer: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy, Honoraria; ARIAD: Research Funding; MSD: Consultancy, Honoraria; Gilead Sciences: Research Funding; Ono: Consultancy, Honoraria, Research Funding; SymBio: Research Funding; HUYA/IQVIA Services Japan: Consultancy, Honoraria; AbbVie: Consultancy, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Novartis: Honoraria, Research Funding; Otsuka: Honoraria; Sanofi: Honoraria; Solasia Pharma: Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Czuczman:Celgene Corporation: Employment, Equity Ownership. Russo:Celgene Corporation: Employment, Equity Ownership. Hudak:Celgene Corporation: Employment, Equity Ownership; Novartis: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Wade:Celgene: Employment, Equity Ownership. Kahl:ADC Therapeutics: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy; Seattle Genetics: Consultancy. Vitolo:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Yes, these trials discuss off-label clinical trial investigation of lenalidomide plus R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma.

Introduction: The use of PET-CR as a surrogate endpoint would expedite the development of novel therapies and enable better estimates of sample size based on early outcomes of a trial. Previous studies have reported an association between end-of-therapy (EOT) PET results and long-term progression-free (PFS) and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL) patients receiving standard first-line chemoimmunotherapy. We have also previously shown that the overall predictability of PET-CR for PFS and OS in these trials is similar to that in 18 literature-based studies. (15-ICML 2019, P195). To assess the potential for PET-CR as a surrogate endpoint in registration trials, we conducted a prospectively designed individual patient-level-data meta-analysis of available clinical trials. Methods: We synthesized patient-level data from three prospective phase II and III trials (GOYA [NCT01287741], GATHER [NCT01414855], MAYO [NCT00670358]) conducted in previously untreated DLBCL patients, using a Bayesian hierarchical model. We considered the two treatment arms in GOYA (GOYA-R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] and GOYA-G-CHOP [obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone]) separate; hence a total of four arms, excluding patients without baseline PET scans. We investigated the relationship between PET-CR and long-term survival outcomes overall and within patient subgroups. We used Kaplan-Meier plots to compare survival endpoints by PET-CR status. We considered hypothetical RCTs that have PET-CR and PFS as endpoints to show how our model of the relationship between PET-CR and PFS can be used to predict the trial outcome. Results: We included 1496 patients (GOYA-R, GOYA-G, GATHER, MAYO, respectively: 665, 669, 100, 62). EOT PET-CR status was determined by the Lugano criteria in GOYA and by IHP in the other two studies. The overall rate of PET-CR was 72%; respectively 72%, 73%, 62% and 74% per arm. Panel A of the Figure shows Kaplan-Meier plots of PFS by PET-CR status. The Bayesian modeled hazard ratio (HR) comparing PET-CR versus nonCR was 0.13 (95% CI: 0.10, 0.15). The model can be used in planning a clinical trial as follows. Suppose a new therapy improves the PET-CR rate from 70% to 85%. Based on our model the expected HR for PFS treatment effect would be 0.71 (95% CI: 0.58, 0.84). The trial sample size required to demonstrate such an improvement with 90% power is about 650 patients, assuming an accrual rate of 50 patients per month and a minimum follow-up time of 12 months. Panel B of the Figure shows the model-based PFS HR and its CI (shaded) as it depends on the PET-CR rate of the new therapy. This plot also shows the estimated total trial sample size (in red), again assuming the relationship between PET-CR and PFS in our model. However, our model may not apply for the new therapy; and the trial could have an adaptive design with final sample size tailored to the accruing information about PET-CR and PFS and their relationship for the therapies in the trial. Conclusions: Achieving an EOT PET-CR in newly diagnosed DLBCL is highly predictive of favorable outcome in the populations we considered. The estimated HR is 0.13 for PFS, PET-CR versus nonCR, and it is 0.10 for OS. Based on our model, a treatment that improves PET-CR rate could be reasonably expected to have a benefit on PFS and OS, for the populations we considered. Whether a new therapy, with a different mechanism of action, that improves PET-CR rate will extend PFS in a clinical trial is less clear. An adaptive trial could be initiated based on our model as a hypothesis. This hypothesis can be verified or updated using accruing information in the trial itself. Our model can also help in planning clinical trials for re-estimating sample size during the trial and considering early stopping for futility. Further work should investigate the applicability of PET-CR in predicting PFS and/or OS for treatments that have different mechanisms of action and for other populations of patients. Acknowledgements: This work was funded by Genentech/Roche. Disclosures Berry: Berry Consultants, LLC: Consultancy, Employment, Equity Ownership, Other: Berry Consultants, LLC is a company that provides statistical design and analysis services to pharmaceutical companies (including Genentech/Roche), medical device companies, U.S. NIH cooperative groups, patient advocacy groups, and international consortia. Broglio:Berry Consultants LLC: Employment. Ward:Hoffmann La Roche: Employment, Equity Ownership. Mattiello:F. Hoffmann-La Roche Ltd: Employment. Sahin:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. McGlothlin:Berry Consultants, LLC: Consultancy, Employment. Elliott:Berry Consultants, LLC: Employment. Sehn:Lundbeck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Verastem: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen-Ortho: Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Trněný:Abbvie: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Vitolo:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche: Speakers Bureau. Martelli:Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kostakoglu:F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Nowakowski:F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding.

Abstract Background: There remains a critical need to identify untreated HR FL patients (pts) who are at increased risk of early progression and death with conventional treatment. Data examining baseline PET has been reported to be prognostic in FL, however, there remains a paucity of data analyzing this in the context of bendamustine/rituximab (BR) induction followed by maintenance rituximab (MR). We examined the prognostic impact of baseline PET metabolic imaging from the randomized BIONIC study for pts with untreated HR FL. Methods: The BIONIC study conducted by the ECOG-ACRIN Cancer Research Group enrolled untreated grade I/II or IIIa FL pts with HR disease defined as GELF high tumor burden and/or FLIPI score of 3-5. Pts were randomized to: a) standard BR induction x 6 followed by maintenance rituximab (MR) q 2 months x 2 years vs b) bortezomib + BR x 6 followed by MR q 2 months x 2 years vs c) BR x 6 followed by q 2 months MR x 2 years + lenalidomide given concurrently with the first year of MR. Survival analyses showed no significant differences in 4-year progression-free survival (PFS) or overall survival (OS) for any study arm (Evens AM et al, ASH 2017). All pts were thus pooled for the purpose of analyzing baseline PET imaging and other characteristics and for correlation with clinical outcomes. Kruskal-Wallis & Wilcoxon Rank Sum test were used to assess differences in distribution of: metabolic measurements (SUVmax and SUVmean of the dominant mass (i.e., the mass/lesion with the highest SUV uptake); metabolic tumor volume (MTV); and total lesion glycolysis (TLG) by categorical variables); induction treatment response; and end-of-induction (EOI) PET response vis-à-vis Deauville scoring (1-3 = negative). Cox proportional hazards regression was used to correlate these metabolic measurements with PFS & OS and multivariable analyses were conducted. An optimal cutoff threshold (grouping into 'High' or 'Low' categories) was used for the metabolic measurements that were significantly associated with PFS & OS. Results: Metabolic data were received and measurements were analyzed centrally on 182 (71%) of 257 eligible pts. The EOI overall response rate (ORR) for all pts on study was 92% with a complete remission (CR) rate of 73%. Additionally, 12% of pts experienced early progression of disease (POD) within 2 years. SUVmax was borderline for association with PFS (P=0.06) and MTV and TLG were not associated with PFS or OS. We demonstrated a statistically significant linear relationship between continuous SUVmean score with PFS and OS, and thereafter, used the minimum p-vlaue approach to determine the optimal cutoff threshold of 7.03 to group pts into 'High' and 'Low' risk groups; with this threshold, baseline SUVmean of the dominant mass was categorized as high risk in 27% pts. The 4-year PFS rates for SUVmean low vs high groups were 80% (95% CI 72, 90%) vs 55% (40, 74%), respectively, P<0.001; and the corresponding 4-year OS rates were 93% (89, 98)% vs 80% (95% CI 69, 93%), respectively, P=0.01 (see Fig. 1). Sensitivity analyses showed no differences in baseline SUVmean by study arm, GELF or FLIPI. The only clinical characteristic that varied among patients with low vs high baseline SUVmean was Black race (0.8 vs 8.0%, respectively, Chi-square P=0.08); there were no other differences based on age, sex, stage, FLIPI, GELF status, ECOG PS, LDH, or # of extranodal sites. In addition, baseline SUVmean correlated with EOI PET (negative EOI PET with baseline SUVmean Low vs High: 81% vs 62%, respectively, P=0.03). In multivariable analyses, both baseline SUVmean and EOI PET remained significant (SUVmean: PFS HR 2.62 (95% CI 1.40-4.92), P=0.001, OS HR 2.37 (95% CI 1.01-5.56), P=0.02; EOI PET PFS HR 4.70 (95% CI 2.74-9.54), P<0.001, OS HR 2.78 (95% CI 1.18-6.56), P=0.01). Finally, baseline SUVmean was also strongly predictive of FL pts who experienced early 2-year POD (Chi-square P<0.001). Conclusions: High baseline SUVmean of the dominant mass was a strong independent prognostic factor for survival for untreated HR FL pts treated with BR-based induction with rituximab maintenance and significance was independent of FLIP or GELF criteria. Collectively, this represents a novel and simple method to identify FL pts at increased risk of early POD and poor survival with standard therapy. Continued investigation of combined PET imaging analyses and other correlative studies to enrich prognostication are warranted. Disclosures Hong: Merck: Consultancy. Advani:Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Infinity: Other: Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Millenium: Other: Institutional Research Support; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Autolus: Other: Consultancy/Advisory Role; Takeda: Other: Consultancy/Advisory Role; Celgene: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; AstraZeneca: Other: Consultancy/Advisory Role; Cell Medica: Other: Consultancy/Advisory Role; Gilead/Kite: Other: Consultancy/Advisory Role; Agensys: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Janssen Pharmaceutical: Other: Institutional Research Support. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kahl:Acerta: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Juno: Consultancy; CTI: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy. Evens:Affimed: Consultancy; Novartis: Consultancy; Acerta: Consultancy; Bayer: Consultancy; Tesaro: Research Funding; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy.