FLYER: Phase III Trial of R-CHOP x 4 Followed by Rituximab x 2 vs Standard R-CHOP x 6 in Younger Patients With Favorable-Prognosis DLBCL Integrating New Malignant Hematology Findings Into Practice: Independent Conference Coverage of ASH 2018* December 1-4, 2018; San Diego, California *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; DLBCL, diffuse large B-cell lymphoma; R, rituximab. Supported by educational grants from AbbVie, AstraZeneca, Celgene Corporation, Dova Pharmaceuticals, Incyte, Jazz Pharmaceuticals, Novartis Pharmaceuticals, Pharmacyclics, Seattle Genetics, and Takeda Oncology.

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R-CHOP x 4 Followed by Rituximab x 2 vs R-CHOP x 6 in Favorable-Prognosis DLBCL (FLYER): Background Addition of rituximab to 6 cycles of CHOP or CHOP-like chemotherapy significantly improved survival outcomes in younger patients with previously untreated, low- risk DLBCL[1] 3-yr PFS rate: 85% with addition of rituximab vs 68% with chemotherapy alone (log-rank P < .0001) Benefit greatest in subgroup with favorable prognosis, defined by nonbulky disease and age-adjusted IPI = 0 Reducing number of CHOP cycles may maintain efficacy while decreasing toxicity Current analysis evaluated noninferiority of R-CHOP x 4 cycles followed by rituximab x 2 cycles vs standard R-CHOP x 6 cycles in younger patients with aggressive B-cell NHL and favorable prognosis[2] CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; DLBCL, diffuse large B-cell lymphoma; IPI, International Prognostic Index; NHL, non-Hodgkin lymphoma; R, rituximab. Slide credit: clinicaloptions.com 1. Pfreundschuh. Lancet Oncol. 2006;7:379. 2. Poeschel. ASH 2018. Abstr 781.

FLYER: Study Design International, randomized phase III noninferiority trial R-CHOP x 4 cycles followed by Rituximab x 2 cycles (n = 293) Patients with untreated aggressive B-cell lymphoma, aged 18-60 yrs, stage I/II disease, age-adjusted IPI = 0, no bulky disease (maximum diameter < 7.5 cm) (N = 588) R-CHOP x 6 cycles (n = 295) Primary endpoint: PFS, 3-yr PFS rate Assumed 3-yr PFS rate of 93% with R-CHOP x 6 Difference up to -5.5% allowed with R-CHOP x 4 → R x 2 while still proving noninferiority with 80% power and 1-sided α = 0.05 (planned sample size: N = 592, assuming 10% loss yields final N = 532) Other endpoints: response, EFS, OS, safety CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; IPI, International Prognostic Index; R, rituximab. Slide credit: clinicaloptions.com Poeschel. ASH 2018. Abstr 781.

FLYER: Baseline Characteristics R-CHOP x 4 → R x 2 (n = 293) R-CHOP x 6 (n = 295) Female, n (%) 118 (40) 116 (39) Median age, yrs (range) 49 (18-60) 47 (19-60) Stage, n (%) I II III/IV 174 (59) 117 (40) 2 (1) 172 (58) 119 (40) 4 (1) Age-adjusted IPI, n (%) 1 291 (99) 4 (1) Extralymph. involvement, n (%) 95 (32) 96 (32) Bulky disease, n (%) 1 (0.3) B symptoms, n (%) 27 (9) 9 (3) Pathology R-CHOP x 4 → R x 2 (n = 257) R-CHOP x 6 (n = 251) DLBCL, % Centroblastic Immunoblastic Plasmoplastic Anaplastic large cell T-cell–rich B-cell lymphoma NOS Prim. mediast. B-cell lymphoma 78 40 2 0.4 1 32 80 44 34 Follicular lymphoma IIIB/III + DLBCL, % 5/9 3/10 Burkitt lymphoma, % MCL (blastoid), % Aggressive MZL, % NOS, % Unclassified (insufficient material), % CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index; LDH, lactate dehydrogenase; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NOS, not otherwise specified; PS, performance status; R, rituximab. No patients had LDH > UNV or ECOG PS > 1 Significantly higher frequency of B symptoms at baseline in R-CHOP x 4 → R x 2 arm (P = .002) Slide credit: clinicaloptions.com Poeschel. ASH 2018. Abstr 781.

FLYER: PFS (Primary Endpoint) 1.0 0.8 0.6 Proportion With PFS Patients, n 293 295 36-Mo PFS, % (95% CI) 96 (94-99) 94 (91-97) 0.4 R-CHOP x 4 → R x 2 R-CHOP x 6 0.1 CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; f/u, follow-up; R, rituximab. 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 Mos After median f/u of 66 mos, PFS noninferior with R-CHOP x 4 → R x 2 vs R-CHOP x 6 Slide credit: clinicaloptions.com Poeschel. ASH 2018. Abstr 781. Reproduced with permission.

FLYER: Response, EFS, OS (Secondary Endpoints) Outcome R-CHOP x 4 → R x 2 (n = 293) R-CHOP x 6 (n = 295) Response, % CR/CRu PR No change Progression Unknown CR/CRu and additional tx 91 1 5 2 92 0.3 36-mo EFS rate, % (95% CI)* 89 (86-93) 89 (85-92) 36-mo OS rate, % (95% CI)† 99 (98-100) 98 (96-99) CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; CRu unconfirmed CR; EFS, event-free survival; f/u, follow-up; R, rituximab; tx, therapy. *Median f/u: 65 mos. †Median f/u: 67 mos. Comparable rates of efficacy with R-CHOP x 4 → R x 2 vs R-CHOP x 6 Slide credit: clinicaloptions.com Poeschel. ASH 2018. Abstr 781.

FLYER: Cumulative Incidence of Relapse 0.20 Patients, n 267 271 538 Relapse, n (%) 11 (4) 13 (5) 24 (4) 1.18 0.16 R-CHOP x 4 → R x 2 R-CHOP x 6 Total 0.14 0.12 Proportion 0.10 0.08 0.06 0.04 P = .679 0.02 CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; f/u, follow-up; R, rituximab. 20 40 60 80 100 120 140 Mos Relapse rates similar with R-CHOP x 4 → R x 2 vs R-CHOP x 6 with longer f/u Slide credit: clinicaloptions.com Poeschel. ASH 2018. Abstr 781. Reproduced with permission.

FLYER: Safety AE, n R-CHOP x 4 → R x 2 (n = 293) R-CHOP x 6 (n = 295) Any Grade Grade 3/4 Hematologic AEs Leukocytopenia* 171 80 237 110 Anemia* 107 2 172 8 Thrombocytopenia* 16 5 17 7 Nonhematologic AEs 835 46 1295 70 Paresthesia 227 12 370 14 Nausea 195 6 319 Infection 98 20 156 23 Vomiting 56 1 117 Mucositis 68 105 3 AE, adverse event; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; CT, chemotherapy; R, rituximab. *Blood counts between CT cycles available in 73% of cycles for R-CHOP x 4 → R x 2 vs 69% of cycles for R-CHOP x 6. Nonhematologic AEs with R-CHOP x 6 reduced by approximately one third with R-CHOP x 4 → R x 2 Therapy-associated mortality rate was 0% with R-CHOP x 4 → R x 2 vs 1% with R-CHOP x 6 Slide credit: clinicaloptions.com Poeschel. ASH 2018. Abstr 781.

FLYER: Conclusions In younger patients with aggressive B-cell lymphoma and favorable prognosis, first-line treatment with R-CHOP x 4 → R x 2 showed noninferior PFS, EFS, and OS vs standard R-CHOP x 6 36-mo PFS rate: 96% with R-CHOP x 4 → R x 2 vs 94% with R-CHOP x 6 Nonhematologic AEs were decreased by approximately one third with R-CHOP x 4 → R x 2 vs R-CHOP x 6 Number of any-grade nonhematologic AEs (grade 3-4): R-CHOP x 4 → R x 2, n = 835 (46); R-CHOP x 6, n = 1295 (70) Both arms exhibited comparable relapse patterns and rates Relapse rate was 4% with R-CHOP x 4 → R x 2 vs 5% with R-CHOP x 6 AE, adverse event; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; EFS, event-free survival; R, rituximab. Slide credit: clinicaloptions.com Poeschel. ASH 2018. Abstr 781.

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