Table 1.

Overview of preclinical and clinical studies with venetoclax

Tumor typeCombination agent(s)Preclinical reference(s)Key preclinical findingsKey clinical findingsClinical study (NCT #) clinical reference(s)
CLLMonotherapy(33, 44, 51)Venetoclax exhibits potent killing of patient-derived CLL cells ex vivo while sparing platelets; BCL2 inhibition sufficient to suppress neutrophil colony formation ex vivoORR: 79%, CR: 20%, MRD negativity: 5% in relapsed/refractory CLL (n = 116); grade 3/4 thrombocytopenia: 12%; grade 3/4 neutropenia: 41%. Clinical TLS in 3/56 (1 lethal) in escalation and 0/60 in the 400-mg expansion cohort.M12-175 (NCT01328626) (52)
CLLRituximab(33)Venetoclax–rituximab combination more efficacious than either agent alone in B-cell lymphoma xenograft modelsORR: 86%, CR: 51% in R/R CLL (n = 49); MRD negativity (bone marrow): 57%, 80% of CR Pts (20/25); grade 3/4 neutropenia: 53% (26/49)M13-365 (NCT01682616) (54)
CLLObinutuzumab(55)Venetoclax–obinutuzumab combination demonstrates efficacy superior to either agent alone in three xenograft modelsORR: 100%, CR: 58%, in previously untreated CLL (n = 12); MRD negativity (peripheral blood): 92% (11/12); grade 3/4 neutropenia: 58% (7/12)CLL14 (NCT02242942) (56)
CLLIbrutinib(59, 148, 149)CLL cells from Pts after ibrutinib dosing are highly sensitive to venetoclax-mediated killing ex vivoMedian CLL counts in blood went from 45 × 109/L to 60 × 109/L after 8 weeks ibrutinib, then to 0.042 × 109/L after 8 weeks ibrutinib + venetoclax in relapsed/refractory CLL Pts (n = 35)CLARITY (ISCRTN13751862) (150)
NHLMonotherapy(33, 61)BCL2 translocation t(14;18) or amplification predicts sensitivity of NHL cell lines to venetoclax in vitro; BCL2 protein expression correlates with greater sensitivityORR: 44% (MCL, 75%; FL, 38%; DLBCL, 18%) in Pts with relapsed/refractory NHL (n = 106); grade 3/4 events: anemia (15%), neutropenia (11%), thrombocytopenia (9%). No clinical TLS.M12-175 (NCT01328626) (62)
NHLRituximab(33)Venetoclax enhances the efficacy of rituximab in NHL xenograft modelORR: 30% (n = 53) ven + R in relapsed/refractory FL; grade 3/4 neutropenia: 25% (n = 52)BO29337/CONTRALTO (NCT02187861) (151)
NHLBendamustine + rituximab(33, 69)Venetoclax enhances the efficacy of BR in xenograft and systemic models of NHLORR: 65% (n = 48) in relapsed/refractory NHLM12-630 (NCT01594229) (152)
ORR: 75% (n = 51) in relapsed/refractory FL; grade 3/4 neutropenia: 61% (n = 49)BO29337/CONTRALTO (NCT02187861) (151)
NHLR-CHOP(33)Venetoclax enhances theefficacy of R-CHOP in xenograft model of NHLORR: 88% (n = 24) venetoclax + R-CHOP in NHLs; grade 3/4 neutropenia: 54%GO27878/CAVALLI (NCT02055820) (153)
MCLIbrutinib(70)Venetoclax and ibrutinib demonstrate synergistic killing of MCL cell lines and patient samplesORR: 71%, CR: 63% in Pts with relapsed (n = 23) or treatment-naïve (n = 1) MCL; MRD negativity (bone marrow of CR patients): 80%; grade 3/4 neutropenia: 25%; TLS in 2 PtsAIM (NCT02471391) (71)
ALL (B-cell)Monotherapy(120, 121)B-cell precursor ALL cell lines and PDX models sensitive to venetoclax; MLL–AF4 drives BCL2 expression and sensitivity to venetoclaxNo data yet reportedM13-833 (NCT03236857)—pediatric
ALL (ETP)Monotherapy(117–119)ETP–ALL cell line (LOUCY) and patient samples highly sensitive to venetoclax-mediated killingNo data yet reportedM13-833 (NCT03236857)—pediatric
ALLMonotherapy(121)Pediatric ALL PDX models more sensitive to BCL2/BCLXL inhibitor navitoclax than to venetoclaxNo data yet reportedM16-106 (NCT03181126) venetoclax combination with navitoclax and chemotherapy
AMLMonotherapy(44, 93)High proportion of AML cell lines and patient samples sensitive to venetoclax; efficacy observed in xenograft and PDX modelsORR: 19% (n = 32) in relapsed/refractory AML; grade 3/4 febrile neutropenia: 31%, No TLSM14-212 (NCT01994837) (98)
AML (IDH1/2 mutated)Monotherapy(95)IDH1- and IDH2-mutated AML cells identified as highly sensitive to venetoclaxRR: 33% (4/12) in IDH1/2 mutant tumorsM14-212 (NCT01994837) (98)
AMLCytarabine(154)Venetoclax and cytarabine demonstrate synergistic killing of AML patient samples ex vivoORR: 61%, CR/CRi: 54% (n = 61) in treatment-naïve AML Pts ≥65 years of age and unfit for standard induction therapyM14-387 (NCT02287233) (102)
AMLIdarubicin(155)Idarubicin reduces MCL1 expression and synergizes with venetoclax to kill AML cell linesNo data yet reportedNCT03214562 NCT03194932—pediatric
AMLIdasanutlin(111, 112)Venetoclax significantly enhances the efficacy of idasanutlin and extends survival in subcutaneous and systemic xenograft models of AMLNo data yet reportedGH29914 (NCT02670044)
AMLCobimetinib(104)Venetoclax and cobimetinib demonstrate synergistic killing of AML cell lines and patient samples ex vivoNo data yet reportedGH29914 (NCT02670044)
AMLAzacitidine(99, 100)Venetoclax and azacitidine demonstrate synergistic killing of AML patient samples ex vivoORR: 64% (n = 50) for venetoclax + azacitdine in treatment-naïve AML Pts ≥65 years of age and ineligible for standard induction therapy; no TLSM14-358 (NCT02203773) (101)
MDSMonotherapy(113, 114)ABT-737 extends survival in NRASD12/BCL2 transgenic model of MDS–AML transition; high-risk MDS and secondary AML patient samples sensitive to venetoclax-mediated killing ex vivoNo data yet reportedM15-522 (NCT02966782) ± azacitidine in higher-risk MDS Pts after HMA failure
M15-531 (NCT02942290) + azacitidine in treatment-naïve higher-risk MDS Pts
MMMonotherapy(84, 86)t(11;14)-positive cell lines and MM patient samples highly sensitive to venetoclax; high BCL2/MCL1 mRNA ratio predicts sensitivityORR: 21% (n = 66); RR for t(11;14)-positive: 40% (n = 30); grade 3/4 thrombocytopenia: 32%, grade 3/4 neutropenia: 27%M13-367 (NCT01794520) (85, 156)
MMBortezomib(77)Venetoclax enhances the efficacy of bortezomib in multiple xenograft models of multiple myelomaORR: 67% (n = 66); RR for Pts not refractory to bortezomib with 1–3 prior therapies: 97% (n = 30); grade 3/4 thrombocytopenia: 29%M12-901 (NCT01794507) (78)
MMDexamethasone(157)Dexamethasone induces increased BCL2 priming with BIM and synergistic killing of MM cell linesNo data yet reported—venetoclax + dexamethasone expansion being performed in t(11;14) PtsM13-367 (NCT01794520) (85)
WMIbrutinib(158)Venetoclax synergizes with ibrutinib to kill WM cell lines and patient samples ex vivoNo data yet reported 4/4 Pts had PR (monotherapy)A15-751 (NCT02677324) M12-175 (NCT01328626) (62)
CMLTyrosine kinase inhibitors (ABL)(123)Venetoclax + TKIs kills proliferating and quiescent CML cells, including blast crisis CML samples; kills LSCsNo data yet reportedNo study
BPDCNMonotherapy(126)BH3 profiling identified BPDCN cell lines and patient samples as BCL2-dependent; venetoclax efficacious in PDX models of BPDCNReduction in disease burden within 4 weeks2 patients treated off-label (126)
ER+ breast cancerTamoxifen(128)Venetoclax enhances the efficacy of tamoxifen in PDX models of ER+ breast cancerORR: 31% (n = 13) in Pts with ER+ BCL2+ HER2 metastatic breast cancer; grade 1/2 lymphopenia: 67% (n = 15)m-BEP (ISRCTN98335443) (159)
NBCyclophosphamide(160, 161)Venetoclax active as a single agent vs. some NB cell lines; enhances the efficacy of cyclophosphamide in the PDX modelNo data yet reportedM13-833 (NCT03236857)—pediatric
  • Abbreviations: BPDCN, blastic plasmacytoid dendritic cell neoplasm; BR, bendamustine/rituximab; CR/CRi, complete response/complete response with incomplete recovery of blood count; ER, estrogen receptor; ETP, early T-cell precursor; HMA, hypomethylating agent; LSC, leukemic stem cell; MCL, mantle cell lymphoma; MDS, myelodysplastic syndromes; MM, multiple myeloma; MRD, minimal residual disease; NB, neuroblastoma; PB, peripheral blood; PDX, patient-derived xenograft; Pts, patients; R, rituximab; RR, response rate; R/R, relapsed/refractory; WM, Waldenström's macroglobulinemia.