PF294 IMPROVED OUTCOMES IN PATIENTS (PTS) WITH BCL2‐POSITIVE DIFFUSE LARGE B‐CELL LYMPHOMA (DLBCL) TREATED WITH VENETOCLAX (VEN) PLUS R‐CHOP: RESULTS FROM THE PHASE 2 CAVALLI STUDY
Authors: F. Morschhauser, P. Feugier, I.W. Flinn, R. Gasiorowski, R. Greil, Á. Illés, N.A. Johnson, J.‐F. Larouche, P.J. Lugtenburg, C. Patti, G. Salles, M. Trněný, S. de Vos, F. Mir, M. Kornacker, E. Punnoose, D. Samineni, E. Szafer‐Glusman, A. Petrich, A. Sinha, N. Spielewoy, A. Bazeos, A.D. Zelenetz
Journal: HemaSphere (2019)

Background: BCL2 overexpression, concurrent overexpression of BCL2 and MYC, and coexisting translocations of BCL2 and MYC (double‐hit [DH]) are associated with poor outcome in DLBCL. Ven, a highly selective BCL2 inhibitor, may enhance the current standard regimen of rituximab (R) plus CHOP chemotherapy. The phase (Ph) 1b part of CAVALLI (NCT02055820) established Ven 800 mg, given Days (D) 1−4, Cycle (C) 1 and D1−10, C2−8, as the recommended Ph 2 dose in combination with R‐CHOP in first‐line (1L) DLBCL. Aims: We report safety, efficacy, and biomarker analyses of the Ph 2 part of CAVALLI (data cut‐off, July 13, 2018). Methods: Eligible pts were aged ≥18 years with 1L DLBCL, ECOG performance status ≤2 and International Prognostic Index (IPI) score 2–5. Ven 800 mg was given orally on D1–4, C1 and D1−10, C2−8 combined with R (8 Cs) and CHOP (6−8 Cs); 21‐day Cs. The primary endpoint was positron emission tomography (PET)‐complete response (CR) rate at end‐of‐treatment (EOT; modified Lugano criteria 2014). Secondary endpoints were progression‐free survival (PFS), overall survival (OS), and safety. The R‐CHOP control arm of GOYA (564 pts with IPI 2–5) was selected as a historical control. Factors affecting completion of 8 treatment Cs were assessed using multivariate analysis (MVA). Time‐to‐event endpoints were compared using adjusted Cox regression. Biomarker analyses included BCL2 and MYC expression by immunohistochemistry (IHC; cut‐off, 50% medium/high expression [BCL2] and &gt;40% any expression [MYC]), BCL2 and MYC translocations by fluorescence in situ hybridisation (FISH), and cell‐of‐origin (COO) by NanoString. Results: Overall, 211 pts were enrolled in CAVALLI; 208 received any treatment and were analyzed for efficacy and safety. Baseline characteristics for CAVALLI vs GOYA were similar, but more Ann Arbor Stage IV (65% vs 47%) and BCL2 IHC+ (58% vs 49%) pts were enrolled in CAVALLI. In the overall population, PET‐CR rates at EOT were comparable (CAVALLI, 69%; GOYA, 63%); however, PET‐CR rates were higher in CAVALLI for BCL2 FISH+ and DH pts ( Table ). PFS was improved in the overall and BCL2 IHC+ populations vs GOYA ( Figure ). The PFS benefit in the BCL2 IHC+ population was observed across both ABC and GCB COO subtypes. Evidence of OS improvement vs GOYA was also seen; HR 0.7, 95% CI 0.43–1.1 (overall), HR 0.7, 95% CI 0.35–1.2 (BCL2 IHC+). Grade 3–4 adverse events (AEs) occurred in 86% (179/208) of pts in CAVALLI vs 66% (373/564) in GOYA, mainly cytopenia, febrile neutropenia (FN), and infection. There was a trend towards lower neutropenia and FN/infection incidence in pts receiving granulocyte‐colony stimulating factor prophylaxis. On MVA, age &lt;60 yrs was the only factor to predict completion of 8 treatment Cs (p = 0.002). There were 4 fatal AEs (2%) in CAVALLI vs 30 (5%) in GOYA, but follow‐up was longer in GOYA (29.6 vs 22.3 months). The high rate of AEs in CAVALLI led to Ven and R‐CHOP dose interruptions/discontinuations; 61% of pts received &gt;90% relative dose intensity (RDI) of Ven; 73% received &gt;90% RDI for cyclophosphamide and doxorubicin. The RDI of chemotherapy was similar in GOYA. Summary/Conclusion: Addition of Ven to R‐CHOP in 1L DLBCL resulted in improved efficacy in BCL2 IHC+ pts compared with matched GOYA controls. A higher rate of cytopenia, FN and infections was observed in CAVALLI vs GOYA; however, there was no increase in risk of death, and the RDI of chemotherapy was maintained at similar levels. image